Animal & Veterinary
The Review of Animal Production Drugs by FDA
by Suzanne Sechen, Ph.D., Office of New Animal Drug Evaluation
FDA Veterinarian Newsletter 2006 Volume XXI, No I
When we consider drugs used in animals, we typically think of therapeutic drugs, which, according to the Federal Food, Drug, and Cosmetic Act (FD&C Act), are intended to “diagnose, cure, mitigate, treat, or prevent disease in animals.” However, the FD&C Act also defines a different category of animal drugs as “articles, other than food, intended to affect the structure or function of the body of an animal.” This category includes products known as animal production drugs.
Animal production drugs are administered to animals to enhance the production of edible or non-edible products or to increase the efficiency of a -particular phase of life, including reproduction. Similar to therapeutic animal drugs, animal production drugs must be approved by the Food and Drug Administration (FDA) before they can be used commercially in the United States. By approving animal production drugs, FDA provides livestock producers safe and effective products to improve the productive capabilities of animals on U.S. farms.
Animal production drugs are unique
Animal production drugs are intended for use in healthy animals. Livestock for which production drugs have been approved in the United States include beef and dairy cattle, swine, poultry, and sheep. The products are intended to improve physiological endpoints of importance to the producer. Examples of claims for production drugs approved in the United States include increased rate of weight gain, improved feed efficiency, increased production of saleable milk, increased carcass leanness, and synchronization of estrus.
Most animal production drugs are approved for over-the-counter use. Thus, instructions and information on the label must be clear and complete so that a lay person can use the drug safely. Extralabel use of animal production drugs generally is not allowed.
Review of animal production drugs by FDA
FDA’s Center for Veterinary Medicine (CVM) reviews new animal drugs in the Office of New Animal Drug Evaluation (ONADE). Within ONADE, the Division of Production Drugs is primarily responsible for the review of new animal production drugs. Other Divisions and Teams within ONADE support the review, including the Division of Human Food Safety, Division of Manufacturing Technologies, the Biometrics Team, and the Environmental Safety Team.
Before a new animal drug receives FDA approval, a sponsor must show that it is safe and effective. Safety covers three areas: human, animal, and environmental. Most animal production drugs are intended for food-producing animals. Thus, a drug sponsor must test the edible products from treated animals (e.g., meat, milk, and eggs) for safety to human consumers and demonstrate that edible products are free of unsafe drug residues. In addition, sponsors determine the safety of the drug to people handling and administering it to animals. Sponsors must show that a new animal drug is safe to the treated animal. They also determine the impact of the production and use of the drug on the environment. Effectiveness means that the drug does what the sponsor claims, e.g., increases rate of weight gain. In addition to demonstrating safety and effectiveness, a sponsor must demonstrate its ability to manufacture the drug product to a consistent potency and purity.
The FD&C Act does not address the “societal need” for an animal drug or the drug’s economic impact. Therefore, by law, FDA cannot consider these issues when deciding whether to approve a new animal drug. Once FDA determines that an animal drug is safe and effective, the U.S. marketplace tends to decide these elements.
Investigational use of new animal drugs
The drug sponsor conducts studies to evaluate the safety and effectiveness of a new animal drug, as well as the sponsor’s capability to manufacture the animal drug. The sponsor also develops analytical methods to detect and measure drug residues in edible animal products.
Unapproved drugs are illegal to use. However, a drug sponsor is permitted to conduct investigational studies using an unapproved new animal drug so long as the sponsor complies with applicable investigational regulations found at 21 CFR (Code of Federal Regulations) Part 511. A sponsor notifies CVM of shipment/delivery of the drug for clinical investigations by submitting to an Investigational New Animal Drug file (INAD) a notice of shipment, which includes information such as the location of studies, number of animals treated, doses, and duration of treatment. A sponsor may also request authorization to market food from the large number of investigational animals typically needed to evaluate the safety and effectiveness of a new animal production drug. CVM will authorize the use of the food products of investigational animals only if the food products are determined to be safe for human consumption.
CVM oversees a sponsor’s investigational activities with a new animal drug in several ways. Although not required, most sponsors typically submit protocols of their proposed safety and effectiveness studies for CVM scientists to review before conducting the studies. CVM scientists provide recommendations on factors such as study design, animal numbers, management of study animals, variables to be measured, and proper statistical analysis. This input increases the likelihood that a study will provide the data needed by CVM to determine if the drug is approvable.
FDA has developed standards by which safety studies are to be conducted. These are known as the Good Laboratory Procedures (GLP). In addition, CVM has developed standards for clinical animal studies (typically the effectiveness study), called Good Clinical Practices (GCP). These standards address issues such as appropriate expertise and responsibilities of study personnel, the need for quality assurance procedures, general study design, procedures to reduce potential bias in results, and study documentation. By following the GLP and GCP standards, drug sponsors improve the accuracy, integrity, and correctness of data from their safety and effectiveness studies.
FDA has a Bioresearch Monitoring Program by which CVM scientists inspect safety and effectiveness studies of animal drugs while they are conducted. This program provides CVM scientists firsthand information on conduct of the study, health and appearance of study animals, and quality of data collection.
Once safety and effectiveness studies are completed, sponsors submit not only summary reports to CVM, but all the data collected during the studies. CVM scientists examine the data to ensure that all study animals are accounted for and were properly managed. They also examine whether there were problems such as extensive missing data and/or biologically unusual results. These factors help CVM scientists determine whether a study is acceptable to evaluate the safety and/or effectiveness of the drug. In addition, CVM statisticians determine whether the data were properly summarized and analyzed.
Evaluating the effectiveness of new animal production drugs
Effectiveness studies of new animal production drugs are well-controlled studies designed to determine whether the product achieves its proposed claims under expected use conditions. The effectiveness study may also contribute information regarding the drug’s safety and information for product labeling that is helpful to the potential user of the drug.
Drug sponsors will typically choose study locations that are major production areas in the United States for the species/class of animal and type of production being evaluated. Research or commercial farms may be used. A sufficient number of normal, healthy animals representative of their production class are assigned to the study to provide adequate statistical power to evaluate the proposed claims.
The new animal production drug is administered to study animals as it is intended to be used. For example, the drug might be administered in the feed, injected, or implanted under the skin. If a sponsor is seeking approval of a single dose of the new animal production drug, treatment groups will consist of the intended dose and an appropriate control group. The sponsor may instead choose to seek approval of a dose range, in which case several doses will be included in the study in addition to a control group. Treatment and control group assignments are concealed from study personnel so that all study animals are handled in a consistent manner throughout the study to minimize bias.
Effectiveness studies for new animal production drugs are conducted until animals are marketable, for an appropriate portion of the production cycle, or for a period of time sufficient to determine the effect on a reproductive claim. For example, for claims associated with meat production, treatment will usually be conducted until animals reach a terminal weight (slaughter or market). For dairy production claims, treatment will usually encompass at least a complete lactation cycle and a portion of the subsequent lactation.
Effectiveness studies for new animal production drugs incorporate common U.S. commercial management practices for the species and class of animal and study location, such as housing and feeding, while maintaining a well-controlled study. Invasive measures, such as routine blood collection, are usually avoided during the effectiveness study, so as not to affect the response of the study animals to treatment.
In addition to measuring data associated with the claims of interest, other production variables or animal product quality may be measured. For example, for a production drug intended to increase carcass leanness, economically important factors such as weight gain, feed efficiency, or meat quality may be measured to determine if there are any negative effects.
The safety of a new animal production drug to the treated animal is determined in part from non-clinical target animal safety studies. However, effectiveness studies for new animal production drugs also provide considerable information on the effects of the drug on animal health. The large number of animals often used in effectiveness studies provides power to detect low frequency adverse events. Effectiveness studies also provide information on the health of animals treated with the production drug under conditions similar to commercial practices. Thus, all animals in an effectiveness study should be observed at least daily for all signs of illness, such as reduced feed intake, lameness, abnormal respiration, reproductive abnormalities, mastitis, or injuries. Necropsies are performed on all animals that die or are euthanized.
Approval of a new animal production drug
CVM scientists first determine if studies conducted and submitted by the sponsor to evaluate the safety and effectiveness of a new animal production drug are acceptable and that data were properly summarized and statistically analyzed. Once these initial determinations have been made, CVM scientists will review all results and determine if the drug is safe and effective.
CVM may determine that a new animal production drug is not safe and/or effective or that more data are needed to reach conclusions about it. More specifically, CVM scientists will determine not only if the proposed claim (for example, increased rate of weight gain) is statistically significantly improved by treatment with the new animal production drug, but also whether the amount of the improvement is biologically meaningful (in terms of livestock production). Similarly, CVM scientists will examine the effect of the drug on other production and animal health variables that were measured during the study to determine if there were any negative effects associated with use of the production drug. If any adverse reactions are severe, it may be determined that the drug is not safe.
The labeling on an approved drug communicates important information gathered from the safety and effectiveness studies. Once a new animal drug is determined to be approvable, CVM scientists will review proposed product labeling to make sure that it accurately describes the approved claim and clearly describes how to properly use the drug. This information includes any withdrawal period necessary before food products from treated animals may be used for human consumption. Product labeling also includes information on adverse effects that might be increased in treated animals but that are not so severe to prevent approval of the product, plus any approaches to minimize these risks. To further describe the basis for deciding that the drug is safe and effective, CVM also makes available to the public a Freedom of Information Summary.
The FDA’s thorough review of new animal production drugs ensures that only safe and effective products are available to U.S. livestock producers. These products in turn provide livestock producers safe and effective approaches to improve the productive capabilities of animals on their farms and help to ensure a plentiful food supply.