Groups resistant to FDA guidelines; consumer groups want more controls

Rockville, Md.-The Food and Drug Administration's (FDA) plan to curb antibiotic resistance through greater controls on veterinary drugs is being met with some opposition from industry groups.

Dr. Linda Tollefson

At presstime, the American Veterinary Medical Association (AVMA), the Animal Health Institute (AHI) and various agriculture groups were formulating formal positions that will be submitted to FDA's Center for Veterinary Medicine (CVM) on Nov. 27. The positions are in response to new risk assessment guidelines that will be considered when approving a new, or existing, antibiotic for use in agriculture. Consumer groups plan to formulate opinions on the subject too, and contend the agency is not going far enough to control antibiotic use in agriculture.

New safeguard

The guidelines are the agency's attempt to add a new safeguard to combat antibiotic resistance.

The document outlines a detailed risk assessment methodology used on antibiotics prior to FDA approval for use in agriculture. The agency also plans to apply this risk assessment to already approved veterinary antibiotics, Dr. Linda Tollefson, deputy director of FDA's Center for Veterinary Medicine, tells DVM Newsmagazine.

The draft guideline summarizes the issue this way: "The FDA believes that human exposure through the ingestion of resistant bacteria from animal-derived foods represents the most significant pathway for human exposure to resistant determinants (or resistant bacteria) that have emerged as a consequence of antimicrobial drug use in animals."

Dr. Lyle Vogel

The long-term impact of this guidance is unclear, officials say. Uncertainty breeds fear. A shift from approving antibiotics over-the-counter to a prescription or veterinary feed directive classification is most likely imminent for new and possibly existing antibiotics.

One risk management strategy identified by FDA is to possibly prohibit extra-label use of veterinary drugs in certain circumstances, which is of great concern to the AVMA.

And while this guidance document is squarely focused on food animals, every veterinary practitioner from companion animal to equine, should take notice, says Dr. Lyle Vogel, director of scientific activities for the AVMA.

"Looking at scientific reports it is becoming evident that there is a potential there that resistant bacteria are being transferred between companion animals and humans, and possibly in both directions. The public health authorities and regulators are going to start looking at that if it appears to be a significant risk."

Risk assessment is needed

FDA says that adding a risk assessment strategy is needed to help safeguard human health and keep these drugs effective for human use.

"Minimizing the risk of antimicrobial resistance is in the best interest of everyone," Tollefson says.

Alexander Mathews

She explains this risk assessment process is necessary to keep new products coming to market. She adds that the likely outcome of having a formal process in place to assess the risks of resistant pathogens impacting humans through the use of antibiotics for agriculture will actually help spur approvals by adding new safeguards to the system.

Industry couldn't disagree more.

Ripple effect

Dr. Tom Burkgren, executive director of the American Association of Swine Veterinarians, fears that products will be lost to veterinarians and producers as a result. Vogel also thinks agriculture will lose some antibiotics.

Burkgren explains: "Overall, there is such a high degree of subjectivity built into the guidance document, the devil is really going to be in the details. How they apply this guidance is key. They could be very flexible in their application of this, or they could take a more draconian method and apply it very restrictively. The result could be they stop approving drugs, and we could have current drugs approval removed or labels changed. That is our fear," he says.

Even more ominous could be the response from manufacturers, which could impact all areas of the veterinary profession.

"I think there are going to be products that will not be defended," Burkgren says. "I think the higher volume, low margin products will not be defended. And all we will be left with are the high margin, low volume products," he adds.

Greatest risk?

What classes of antibiotics are at greatest risk to agriculture? Fluoroquinolones, growth promotants and any antibiotic used in feed or water for more than six days in duration are all at risk for FDA intervention, he adds. There is already FDA action to remove Baytril from the poultry market, as reported in DVM Newsmagazine, but manufacturer Bayer is contesting the move in court.

Table 1

Tollefson adds that FDA is committed to the protection of animal health too, and did most recently approve an entirely new antibiotic compound, danofloxacin mesylate, for Pfizer for treatment of bovine respiratory disease in beef.

But for swine practitioners, removing the ability to medicate from a population-based (metaphylaxis) method is very significant to modern agriculture.

Air it in public

At presstime, FDA convened a public meeting to gather input on the proposed draft guidance for industry entitled, "Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to their Microbiological Effects on Bacteria of Human Health Concern." About 150 people were in attendance, CVM reports.

Tollefson says that the agency will take all this information into consideration and a final guidance will be issued tentatively slated for the spring of 2003.

FDA says: "Risk: FDA's overriding concern is that the effectiveness of antimicrobial drugs is decreased or lost in humans as a consequence of human exposure to resistant bacteria (or resistant determinants) resulting from the use of antimicrobial drugs in food-producing animals."

The new guidelines outline a risk analysis methodology as a "process for evaluating antimicrobial resistance concerns as part of the pre-approval safety evaluation of a new animal drug. These guidelines also allow the agency to review existing antibiotics on the market to re-evaluate the potential for causing antimicrobial resistance.

What does it mean?

If Tollefson had one message to communicate to her veterinary colleagues it would be: "Just remember there are risks associated with the use of antibiotics, and that is what the Center is evaluating."

FDA is reviewing veterinary approved antibiotics. But the risk assessment isn't solely geared to the impact of human health; a drug's importance to animal health is weighted two-thirds as heavily in the assessment methodology, she says.

According to the draft document, there are four risk management alternatives including:

• Change status from OTC to prescription only or veterinary feed directive use. "FDA believes that only those drug products that are of low concern with regard to potential impact on human health may be available OTC."

• FDA lists 88 approved antibiotics, only kanamycin, neomycin and bacitracin received a low importance rank to human medicine.

• Prohibit extra-label use of certain drug products, particularly those that are considered of high concern in regard to potential human health impacts.

• Limit extent of use of certain antimicrobial drug products.

• Withdraw approvals of drug products or use conditions of concern.

Opposing views

Leading dissenting views include the Animal Health Institute (AHI), an organization that represents animal health manufacturers.

Alexander S. Mathews, president and CEO of AHI, says, "Conceptually, the use of risk assessment to evaluate products and their potential impact on public health is the correct approach and certainly superior to alternative proposals that simply remove products from the market."

Mathews adds, "The model proposed by CVM significantly raises the regulatory hurdle for approving antimicrobial new animal drugs and is likely to result in fewer options for veterinarians, livestock and poultry producers. As we have learned from Europe, fewer options will result in increased animal disease and compromise food safety."

Mathews calls some of the details in the proposal unnecessarily stringent and "will make it very difficult for new antibiotic products to be approved, thus creating new animal health and food safety risks while not adding to public health."

Ron Phillips, vice president of legislative affairs for AHI, echoes industry concerns about the importance placed on so many antibiotics to human medicine.

Out of the 88 antibiotics listed, three were ranked low importance, 23 were of medium importance and the rest were ranked of high importance.

Because so many antibiotics are ranked high it could unduly influence the risk assessment, Phillips contends.

"We have a concern with how drugs are categorized in importance to human medicine. On the one hand, FDA says the foodborne route is the route of greatest concern as it relates to the potential transfer of resistant bacteria. When they go ahead and categorize the importance of these drugs to human medicine, they take an ultra conservative approach by categorizing almost everything of high importance, regardless of whether or not it is used in the treatment of foodborne illness."

The guidance document also gives "very little direction on what that final ranking means in terms of a drug's ability to be approved by FDA," Phillips says.

"There is just too much uncertainty. They haven't given companies clear guidance on how they will look at this standard of reasonable certainty of no harm, which is the key phrase they use for safety," he explains.

"Does a drug company want to spend tens of millions of dollars to enter a process that is basically a roll of the dice?"

Proponents of increased regulations

Keep Antibiotics Working is a coalition of organizations that is actively lobbying for increased regulations on use of antibiotics in animal agriculture.

The coalition was formed to fight misuse and overuse of antibiotics in agriculture and human medicine. A leading consumer advocacy group, Center for Science in the Public Interest (CSPI) is a major member of this coalition. Other members include the Humane Society of the United States, Sierra Club and Environmental Defense (see Table 1, p. 29).

Recognition increases

Tamar Barlam, MD, an infectious disease physician who is leading the antibiotic resistance project for CSPI, says, "Although it has a number of important limitations, this long-awaited document signals FDA's increasing recognition that overuse of antibiotics in agriculture plays a significant role in the growing public health crisis of antibiotic resistance."

Margaret Mellon, Ph.D, JD, of the Union of Concerned Scientists adds in a prepared statement, "The major weakness is that FDA's new guidance focuses primarily on procedures for reviewing applications for approving additional drugs in the future. While that issue certainly warrants attention, the elephant in the room is the vast quantity of antibiotics already administered to farm animals."

The group also criticizes the lack of timetable for re-evaluation of existing antibiotics, and says the agency needs Congressional intervention to act more quickly.

Keep Antibiotics Working is in favor of legislation introduced by Sen. Edward M. Kennedy (D-Mass.) and Rep. Sherrod Brown, (D-Ohio) to phase out growth promoters. Officials say the legislation will likely be reintroduced during the next session of Congress.