John D. Baker, Susan J. Bright-Ponte, and Lee Anne M. Palmer


FDA Overview

The US Food and Drug Administration (FDA) is a regulatory, science-based federal agency responsible for protecting and promoting the public health through monitoring and regulation of a variety of products necessary for the health and well-being of consumers. The FDA’s jurisdiction includes most food products (other than meat and poultry), animal feed and pet food, human and animal drugs, human dietary supplements, medical devices, veterinary devices, therapeutic agents of biological origin for humans (e.g., vaccines), radiation-emitting products for consumer, medical, and occupational use, cosmetics, and tobacco products.

FDA is an agency within the Department of Health and Human Services and is organized into five major offices under the Office of the Commissioner. The Center for Veterinary Medicine (CVM) and the Center for Food Safety and Applied Nutrition (CFSAN) report directly to FDA’s Office of Foods and Veterinary Medicine (FDA, 2017a).

Center for Veterinary Medicine

Among other things, the Center for Veterinary Medicine is responsible for ensuring that animal drugs, including drugs intended for use in or on animal feed, are safe and effective for their intended uses and that food from treated animals is safe for human consumption. Before a new animal drug can be legally marketed in the United States, it must be approved by the FDA on the basis of quality, safety, and efficacy. When the drug is to be approved for use in food-producing animals, safety to the target animal species must be demonstrated, in addition to safety of food products derived from the treated animals that are intended for human consumption. Once approved products are on the market, the Center monitors the use of the products through surveillance, compliance, and pharmacovigilance programs. Currently, the Center for Veterinary Medicine is organized into six offices. Information about each office and their roles and responsibilities can be found on CVM’s web site (FDA, 2017b).

CVM’s Office of Surveillance and Compliance (OS&C) has primary responsibility for several of the Center’s core functions, including compliance-related actions, postapproval monitoring, and animal feed safety. Within OS&C, the Division of Veterinary Product Safety (DVPS) is responsible for monitoring the safety and effectiveness of marketed animal drugs and devices, and the safety of pet food, through review and analysis of adverse experience reports. The information obtained from review and analysis of these reports helps CVM make decisions about product safety, potentially leading to regulatory actions, label revisions, or other changes necessary to ensure the safe and effective use of a product. Submitted adverse experience reports are maintained in a database used by OS&C to conduct postapproval surveillance and pharmacovigilance activities.

Overview of FDA’s Postapproval Surveillance Program

Although CVM has a rigorous preapproval process for animal drugs, well-conducted randomized controlled clinical trials may not be of sufficient size to identify every safety problem. Once a product is marketed, there is a substantial increase in the number of patients exposed to the drug, including animals with coexisting medical conditions and those being treated with concomitant medications and biologic agents such as vaccines. There are potential food interactions as well. Additional information about medical product safety and effectiveness is obtained after a product is marketed and used under actual field conditions in large diverse populations of animals. This information is used to complete the safety profile of a product and helps to ensure that drug product labeling is adequate and accurate. Ultimately, this information will assist practitioners in making informed decisions to minimize risks while maximizing benefits of the drugs used in animals.

Pharmacovigilance and Adverse Event Reporting at CVM


Pharmacovigilance, as defined by the World Health Organization (WHO), is “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems” (WHO, 2006). The goal of a veterinary pharmacovigilance program is to ensure the continued safety and effectiveness of animal drugs once they are being used in a wide and diverse population of animals.

In general, the role of a pharmacovigilance program is to identify safety signals that, upon further evaluation, may lead to the discovery of previously unidentified or unrecognized adverse drug events and associated risk factors that were not identified in the preapproval evaluation of the product. These adverse events may be related to previously unrecognized pharmacological effects of the drug, idiosyncratic effects, drug–drug interactions, drug–food interactions, drug–disease interactions, factors specific to certain patient populations, individual patient factors, medication errors, product defects, or other factors, such as the reaction being too uncommon to be identified in the small number of animals in which the drug is tested in preapproval studies (CIOMS, 2010). Spontaneous reports of adverse drug experiences, medication errors, and product defects comprise the primary data source upon which CVM’s postapproval pharmacovigilance efforts depend. Also, data from postapproval clinical studies and from the scientific literature may be utilized. Limitations of utilizing spontaneous adverse drug experience (ADE) reporting databases for pharmacovigilance activities include the significant underreporting of ADEs, limited detail in submitted reports, and reporting biases (Strom and Kimmel, 2006). Given the variability in reporting and the many factors that affect reporting, it is well accepted that reporting rates cannot be used to reliably estimate incidence rates of ADEs in the exposed population, and that comparison of reporting rates between products or between countries cannot be used to determine risk. Despite these limitations, the monitoring and evaluation of ADE reports is very important to help ensure that the overall balance of risks and benefits of a particular drug remain acceptable. Additionally, it allows for communication of essential drug safety information to veterinarians and others involved in the treatment of animals.

Adverse Drug Experience – Definition

An adverse drug experience, as currently defined by 21 CFR 514.3, is “any adverse event associated with the use of a new animal drug, whether or not considered to be drug related, and whether or not the new animal drug was used in accordance with the approved labeling (i.e., used according to label directions, or used in an extralabel manner, including but not limited to different route of administration, different species, different indications, or other than labeled dosage). Adverse drug experience includes, but is not limited to:

  1. An adverse event occurring in animals in the course of the use of an animal drug product by a veterinarian or by a livestock producer or other animal owner or caretaker.
  2. Failure of a new animal drug to produce its expected pharmacological or clinical effect (lack of expected effectiveness).
  3. An adverse event occurring in humans from exposure during manufacture, testing, handling, or use of a new animal drug.”

ADE reports submitted to CVM can involve approved or unapproved animal drugs, human drugs used to treat animals, events in humans exposed to animal drugs, and events related to devices used in animals.

Adverse Drug Experience (ADE) Reporting

CVM encourages veterinarians or animal owners who want to report an adverse drug event to an FDA-approved product in an animal or human, to contact the product manufacturer. In the USA, ADE reporting by veterinarians and consumers is voluntary. However, manufacturers and distributors of FDA-approved animal drugs may be subject to the mandatory ADE reporting requirements in 21 CFR 514.80, as discussed further below in this section. All unsolicited reports from veterinarians or consumers, received by the FDA via either the voluntary or mandatory route, are called spontaneous reports.

Consumers and veterinarians can report adverse drug events directly to CVM by downloading a fillable Form FDA 1932a from CVM’s website (FDA, 2017c). This form should be printed and sent or emailed to FDA. Veterinarians and consumers can also report information to CVM by calling the CVM hotline at 1-888-FDA-VETS. In response to the inquiry, CVM can provide a Form FDA 1932a so that it can be completed by the reporter and mailed to CVM. More information about voluntary reporting of adverse events by consumers and veterinarians is available on CVM’s website (FDA, 2017d). The regulations that address the spontaneous reporting obligations for manufacturers and distributors of FDA-approved animal drugs are contained in 21 CFR 514.80, “Records and reports concerning experience with new animal drugs for which an approved application is in effect.”

ADE reports are classified into essentially four categories: (1) 3-day field alerts, (2) 15-day alert initial reports, (3) follow-up reports, and (4) periodic reports.

As defined in 21 CFR 514.80(b)(1), 3-day field alert reports contain information regarding product and manufacturing defects that may result in serious ADEs. Reports of serious, unexpected ADEs are submitted as 15-day alert or “expedited” reports. As required in 21 CFR 514.80(b)(2), these reports must be submitted on Form FDA 1932 to FDA by the applicant within 15 working days of first receiving the information. Follow-up reports are submitted on Form FDA 1932 by the applicant if significant new information is revealed during their investigation of ADEs that are the subject of 15-day alert reports. Reports of ADEs that are not serious and unexpected and reports of product defects that are not expected to result in serious ADEs are submitted in the periodic drug experience report, which is submitted every 6 months for the first 2 years after approval and annually thereafter.

ADE reporting to CVM has increased dramatically over the last decade. CVM received 28,825 ADE reports for the fiscal year 2004 and 91,592 for the fiscal year 2015 (Figure 58.1). Some of the reasons for the significant increase include an increase in number of drug approvals, especially for companion animals, label information providing contact numbers for drug companies, and the interest of the public in reporting perceived product problems. Wide access to the media and internet has also increased the public’s general awareness about drug safety.

Bar graph shows number of adverse drug event on range from FY91 to FY15 versus range from 0 to 100000.

Figure 58.1 Number of adverse drug event (ADE) reports received by CVM from fiscal years (FY) 1991 through 2015.

Approved versus Unapproved Drugs

ADE submission is required only from companies marketing FDA-approved and conditionally (FDA, 2017e) approved animal drugs. Currently, there are no requirements for submitting ADEs for unapproved animal drugs (animal drugs which have not gone through FDA’s approval process) or human drugs used in animals. Exceptions to this are those drugs on FDA’s Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (the “Index”). These drugs are legally marketed for a specific use in certain minor species. Many approved animal drugs can be identified by the presence of a New Animal Drug Application (NADA) number on the label, or an Abbreviated New Animal Drug Application (ANADA) number for generic drugs, or a C-NADA number in the case of conditionally approved drugs, although these identifiers on labeling are not currently required by regulation. Veterinarians and/or animal owners are encouraged to report ADEs for unapproved animal drugs, including compounded products, to CVM using the Form FDA 1932a.

Animal Devices

Though no form of premarket approval is currently required for devices used in veterinary medicine, FDA does have regulatory oversight over veterinary devices and can take appropriate regulatory action if a device is misbranded, mislabeled, or adulterated. A few examples of devices commonly used in animals include suture material, certain types of bandage materials, intravenous catheters, anesthetic machines and equipment, as well as imaging equipment. It is the responsibility of the manufacturer and/or distributor of these articles to assure that animal devices are safe, effective, and properly labeled. Although not required by regulation, CVM accepts reports from manufacturers and distributors of veterinary devices of adverse events associated with marketed devices. Most adverse event reports that CVM receives for animal devices are reported directly by veterinarians or animal owners.

Product Defects

Animal drugs, both prescription and over-the-counter (OTC), must be manufactured in accordance with Current Good Manufacturing Practices (cGMPs) according to regulation. FDA inspects manufacturing facilities before a drug application can be approved. Adherence to cGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of drugs adequately control manufacturing operations.

Reporting Product Defects

A product defect is defined by regulation as “the deviation of a distributed product from the standards specified in the approved application, or any significant chemical, physical, or other change, or deterioration in the distributed drug product, including any microbial or chemical contamination. A manufacturing defect is a product defect caused or aggravated by a manufacturing or related process. These defects are generally associated with product contamination, product deterioration, manufacturing error, defective packaging, damage from disaster, or labeling error. For example, a labeling error may include any incident that causes a distributed product to be mistaken for, or its labeling applied to, another product.” As discussed previously, reporting requirements for product defects are codified in 21 CFR 514.80. Three-day field alert reports involve product defects that may result in a serious adverse event. Product defects that do not have the potential for serious adverse events are reported directly to CVM in periodic reports. Examples of product or manufacturing defects that may result in serious adverse events include, but are not limited to, improperly labeled products, subpotent products leading to lack of effectiveness, superpotent products leading to potential toxicity, lack of sterility or particulate matter in injectable products, and failure of syringe-locking devices leading to accidental overdose of the drug (Bataller and Keller, 1999). Firms work with the appropriate FDA Field Office to accomplish corrective actions for product and manufacturing defects.

Medication Errors

The National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) defines a medication error as “any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing; order communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.”(NCCMERP, 2012). Of these, prescribing errors have been documented to cause the most harm in human patients (Strom and Kimmel, 2006). In 1992, FDA’s Center for Drug Evaluation and Research (CDER) began monitoring human medication error reports that are forwarded to FDA from the United States Pharmacopeia (USP) and the Institute for Safe Medication Practices (ISMP).

In 2008, CVM began a patient safety initiative to prevent medication errors in animals. Medication errors can occur in several settings, including veterinary clinics and hospitals, universities, and human and veterinary pharmacies. Medication errors may occur for a variety of reasons, including, but not limited to:

  • incomplete patient information (for example, not knowing about patients’ allergies, other medicines they are taking, previous diagnoses, and lab results);
  • unavailable drug information (such as lack of up-to-date warnings);
  • miscommunication of drug orders, which can involve poor handwriting, confusion between drugs with similar names, misuse of zeros and decimal points, confusion of metric and other dosing units, and inappropriate abbreviations;
  • lack of appropriate labeling as a drug is prepared and repackaged into smaller units;
  • environmental factors, such as lighting, heat, noise, and interruptions, which can distract health professionals from their medical tasks (AHA, 2015).

Unclear medical abbreviations are one of the most common causes of medication errors.

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Feb 8, 2018 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Pharmacovigilance

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