As the Food and Drug Administration reviews proposed guidance on the use of antibiotics in animal agriculture, thousands of people and organizations have offered public comments to the agency that make a consistent and important point: The draft does not go far enough to establish clear, science-based limits on how long the drugs can be used.
Inappropriate use of antibiotics in agriculture contributes to the spread of antibiotic-resistant superbugs that can threaten human and animal health. One-third of antibiotics approved for use in animals lack any restrictions on prescription duration, which leaves the door open for unnecessarily long treatment courses. Because all antibiotic use contributes to resistance, injudicious use in animals can accelerate the growth of drug-resistant pathogens.
FDA has taken other steps to improve antibiotic use in animal agriculture, including a ban on use of medically important antibiotics for the purpose of growth promotion. In 2018, the agency announced plans to ensure that all animal antibiotics had science-based duration limits, a move that could significantly curb excessive use of these drugs.
However, the preliminary proposal for this guidance, released this year, would not achieve the agency’s stated goal. The plan does not require explicit and well-defined durations of use—the length of time a drug may be used, based on clinical or experimental data—and could permit drugmakers to leave those decisions to the discretion of a veterinarian who may have little data or clinical information on which to base prescribing decisions. Since January, the agency received more than 31,000 public comments on the proposal, with the overwhelming majority asking for more exact parameters for establishing defined, evidence-based limits on duration of use.
To ensure that the measure has its intended effect, FDA should address the substantial arguments laid out in numerous comments before forging ahead with its policy.
Many comments urge the agency to require clear and specific duration limits derived from clinical data. FDA’s current proposal could allow drugmakers to use imprecise metrics when determining how long their drugs can be used on animals, such as an animal’s age or weight. Moreover, drugmakers could rely on a veterinarian’s discretion to determine length of treatment without giving practitioners the necessary data to make informed prescribing decisions.
Additionally, commenters want FDA to speed up its proposed timeline. The agency’s draft guidance allows sponsors six years or more to update their product information. Because FDA does not anticipate finalized wording until 2024, many duration limits may not be implemented until 2030, if not later. Such a timeline fails to reflect the urgency of the threat of antibiotic resistance and allows injudicious practices to persist for years.
Several comments—submitted by animal producers and drug industry and veterinary professional organizations—argue that oversight by veterinarians is sufficient, and that they need significant flexibility in prescribing antibiotics. However, veterinarians rely on drug label instructions to guide prescribing practices; the instructions usually reflect up-to-date information from well-designed scientific and clinical studies.
For many of the drugs that lack duration limits, there is no clear clinical guidance to help veterinarians determine optimal length of therapy based on symptomatic or diagnostic findings. About a quarter of antibiotics that lack a duration limit are used for prevention of disease in animals showing no signs of infection, and almost as many are indicated for disease control, meaning they are used in healthy animals that may have been in contact with an infected animal.
FDA does not specify how drugmakers should establish appropriate durations for these drugs, but preventive or control uses should be reserved for exceptional cases when animals are particularly vulnerable to infection. When antibiotics are used for these purposes, veterinarians cannot reference clinical metrics such as resolution of symptoms to determine the optimal length of treatment. Moving forward, drugmakers should clearly identify appropriate lengths of time—derived from clinical or field trial data—indicating the shortest period during which animals are likely to be vulnerable.
Several commenters raised concerns that FDA’s guidance would lead drug companies to withdraw their products from the market, arguing that if companies must perform new research to establish a duration limit, sponsors may decide that the costs are too high and simply end the sales of the needed drugs.
However, there are viable alternative antibiotics—already on the market and FDA-approved for the same uses—for the majority of drugs lacking duration limits. For the drugs with no viable alternatives, FDA should work with drug companies to assess whether additional research is needed. In some cases, companies may already have data from their original studies that can be used to establish a duration of use.
Many comments included concerns about the clinical treatment of anaplasmosis and liver abscesses, which present significant challenges to FDA in finalizing the guidance. These two diseases drive a substantial amount of antibiotic use among cattle and lead to long-term courses of certain antibiotics. For example, research has shown that cattle on feedlots are routinely given the drugs for an average of 135 consecutive days to prevent liver abscesses.
But long-term use is not needed to keep cattle healthy, and other animal management practices can help reduce the need for antibiotics. For example, liver abscesses are a result of high-grain diets and other mostly financially driven management decisions. Improving cattle diet, among other interventions, can help bring down rates of illness. Controlling vectors such as ticks can also help rein in the spread of anaplasmosis, as can separating carrier animals from an uninfected herd.
FDA has already funded studies to investigate appropriate durations of antibiotic use for both of these diseases but has not provided guidance on how drugmakers should use the data, once available, to establish duration limits. As part of this process, the agency should provide specific guidance.
More than 99% of comments submitted to the FDA support the agency’s overarching goal of improving antibiotic stewardship. Implementing clearly defined duration limits for all animal antibiotics is essential to achieving this objective.
FDA should provide specific directions for drugmakers to set evidence-based limits as quickly as is feasible and work with them to determine whether new studies are needed. Together, they should ensure that information on duration of use is fully available to veterinarians within three years. Treating animal diseases can be complex with many different solutions, but improving antibiotic use in agriculture must be a key part of the equation to protect animals and humans from dangerous superbugs.
David Hyun, M.D., is a director and Mark Eichelberg, Ph.D., is a senior associate with The Pew Charitable Trusts’ antibiotic resistance project.