backgrounder
FDA's Approach to Antibiotic Regulation --
"The Framework Document"
Controversy has simmered around the use of antibiotics in food animals for over three decades. Recently, the debate has heated up—increasingly strong evidence is emerging that the practice of giving livestock antibiotics is making some human illnesses once again untreatable, as bacteria which cause the illnesses become resistant to the antibiotics used to treat them.
Under the Food, Drug, and Cosmetic Act, the Food and Drug Administration (FDA) has the authority to restrict the use of antibiotics in animals based upon the potential risk to human health. Historically, concerns about human safety with new agricultural antibiotics focused primarily on ensuring that drug residues in food were safe for human consumption. Now, the FDA plans to extend authority to cover the indirect risks to human health caused by the loss of drugs due to resistance.
Beginning in 1998, the FDA began to restructure its drug-approval system for food-producing animals. In November of that year, the FDA published new guidance, "Guidance for Industry # 78", which spelled out the FDA s intent to take the indirect human health effects of antibiotic resistance into account in the drug-approval process. Later, in January of 1999, the FDA took a second step, releasing the so-called "Framework" document. This draft report outlined the FDA's approach for registering new antibiotics intended for food animals. This risk-based approach attempts to balance the protection of human health against the benefits of antibiotic use in livestock operations.
The FDA's approach is complicated and data intensive. The draft Framework sets out a complex scheme for evaluating and then minimizing adverse human health effects of new animal drugs. New antibiotics first would be categorized by their importance in human medicine and by their proposed use—to determine the potential for human exposure to drug-resistant bacteria if drug-resistance develops from the use of a new antibiotic. This categorization would be used to determine the extent of monitoring programs before and after a new drug is approved for use in food animals by the FDA.
Evaluation of Potential Risk
The FDA's approach categorizes new drugs based upon their importance in human medicine and on the likelihood of human exposure to resistant bacteria. A drug's importance in human medicine would place it in one of three categories. Category I covers drugs essential for treating serious or life-threatening diseases in humans, while Category II covers drugs of choice in the treatment of potentially serious diseases, but for which alternative treatments exist. Category III includes drugs that have little or no use in human medicine. Additionally, the FDA considers that any antibiotic which causes cross-resistance to a drug within one of the three categories, to also be included in that category. The second part of this evaluation - the ranking of the potential exposure of humans to resistant bacteria, either directly or indirectly - is a more difficult task. The approach considers such factors as a drug s attributes (e.g., mechanisms by which a bacterium develops resistance to that drug), product use (e.g., dose or duration of treatment), and potential human contact (e.g., animal management practices) when categorizing the likelihood of human exposure. Based upon the results of this review, a drug would receive a high, medium, or low classification. The combined results of these two classification schemes would determine which new drugs would require pre-approval studies and post-approval monitoring.
Pre-approval Studies: Predicting Resistance Problems
The FDA's Framework envisions requiring pre-approval studies only for those antibiotics that appear likely to pose high public health risks on the basis of the classification scheme. Pre-approval studies would provide information about what might happen once a new antibiotic is in use. They would attempt to determine the likelihood of bacteria developing resistance and what changes might be expected to the mix of bacteria in the animal s intestine. With this information, the FDA would try to develop post-approval studies.
The FDA strategy for predicting resistance considers both the quantity of bacteria that could make people ill present in the animal at the time of slaughter (i.e., what is termed the pathogen load) and the number of types of bacteria present in the animal that are drug-resistant (prevalence of resistance).
Pathogen Load:
Generally, antibiotics are given to reduce the quantity of a target bacteria. However, the antibiotic may also disturb the normal balance of bacteria in an animal s stomach. For example, an antibiotic may make an animal well by decreasing the class of bacteria causing its illness, but may at the same time increase a type of bacteria that can infect people a human pathogen. Animals carrying large amounts of a human pathogen at the time of slaughter could increase the risk of human illness.
Prevalence of Resistance:
The greatest danger occurs if the human pathogens are resistant to antibiotics. When assessing prevalence of resistance, the FDA would want information in both human pathogens and nonpathogenic bacteria. Antibiotic resistance can develop in bacteria that do not cause human illness and, in some circumstances, these nonpathogenic bacteria may transfer their genes for drug resistance to bacteria that cause human diseases.
Post-approval Studies
The Framework calls for the post-approval monitoring of new drugs in hopes of being able to take action before the threat to human health develops. After a new antibiotic was approved for use in food animals, the FDA would set both resistant and monitoring thresholds as part of an early warning system for detecting and evaluating resistance development. A resistance threshold is a defined level of drug resistance that a bacterial population could develop before the risk to human health was seen as significant. The monitoring threshold would be the level of antibiotic resistance in a particular bacterium at which the FDA would begin steps to address the development of drug resistance.
Ideally, the FDA would detect resistance development, study its causes, and provide strategies to mitigate resistance development. If researchers could not find alternatives to retard the development of resistance, the Framework envisions withdrawal of a drug from the marketplace. The Framework acknowledges the difficulty of establishing and detecting scientifically based resistance and monitoring thresholds. It also acknowledges that without reliable thresholds, the FDA may not be able to approve new uses of antibiotics.
Existing Drug Approvals
The Framework focuses almost exclusively on the evaluation and approval of new antibiotics, giving scant attention to the review of previously registered drugs. The only reference toward addressing resistance development in existing drugs is a footnote stating that the framework, if finalized and implemented, would also be used for reviewing these antibiotics as resources permit.
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