Adverse Drug Experience: Definition

An adverse drug experience (ADE) is currently defined in the Code of Federal Regulations (21 CFR 514.3) as

ADEs may be further classified as to seriousness and expectedness. 21 CFR 514.3 currently defines a serious adverse drug experience as “an adverse event that is fatal, or life-threatening, or requires professional intervention, or causes an abortion, or stillbirth, or infertility, or congenital anomaly, or prolonged or permanent disability, or disfigurement.” In addition, an unexpected adverse drug experience is “an adverse event that is not listed in the current drug labeling for the new animal drug and includes any event that may be symptomatically and pathophysiologically related to an event listed on the labeling, but differs from the event because of greater severity or specificity. For example, under this definition hepatic necrosis would be unexpected if the labeling referred only to elevated hepatic enzymes or hepatitis.”

Adverse Drug Experience Reporting

CVM directs veterinarians or animal owners who want to report an ADE in an animal or human to contact the product manufacturer. In the United States, 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 later. All unsolicited reports from veterinarians or consumers received by the FDA via either the voluntary or the mandatory route are called spontaneous reports.

ADE Reporting for Veterinarians and Consumers

Consumers and veterinarians can report ADEs directly to CVM by downloading and filling in FDA Form 1932a from CVM’s website (FDA, CVM (a), 2010). This form should be printed and sent to the FDA. Veterinarians and consumers can also report information directly to CVM by calling the CVM hotline at 1-888-FDA-VETS. In response to the inquiry, CVM provides an FDA Form 1932a that can be completed by the reporter and mailed to CVM. At this time there is no electronic submission process available for ADE reports from consumers or veterinarians. More information about voluntary reporting of adverse events by consumers and veterinarians is available on CVM’s website (FDA, CVM (b), 2011).

ADE Reporting Regulations for Drug Manufacturers

The regulations that address the ADE 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.” The regulations impose reporting obligations on drug companies, including manufacturers and distributors, that meet the definition of an “applicant” or “nonapplicant” as defined in 21 CFR 514.3. An “applicant” is defined as “a person or entity who owns or holds on behalf of the owner the approval for an [New Animal Drug Application (NADA)] or an [Abbreviated New Animal Drug Application (ANADA)], and is responsible for compliance with applicable provisions of the act and regulations.” A “nonapplicant” is defined as “any person other than the applicant whose name appears on the label and who is engaged in manufacturing, packing, distribution, or labeling of the product” (21 CFR 514.2). Applicants, including manufacturers and distributors who hold a product’s approved NADA/ANADA, are required to submit all ADE reports to CVM on FDA Form 1932 within certain time frames, as discussed later. As of May, 2010, applicants have the option to submit ADE reports electronically to CVM through the Safety Reporting Portal (SRP) or by the gateway-to-gateway submission process. Nonapplicants, including manufacturers and distributors whose names appear on the product label but that do not hold the product’s approved NADA/ANADA, must forward information about ADEs to the applicant within 3 working days of receiving the information and must maintain records of all reports. If a nonapplicant elects to also report directly to the FDA, the nonapplicant should submit the report on FDA Form 1932 within 15 working days of receiving the information (21 CFR 514.80(b)(3) ). For more information on reporting of adverse drug experiences by drug companies, see CVM’s website (FDA, CVM(c), 2012).

ADE reports are classified into essentially four categories: (1) three-day field alert reports, (2) fifteen-day alert initial reports, (3) follow-up reports, and (4) periodic reports. Three-day field alert reports contain information regarding product and manufacturing defects that may result in serious ADEs (21 CFR 514.80(b)(1) ). The applicant (or nonapplicant through the applicant) must submit the report on paper FDA Form 1932 to the appropriate FDA district office or local field office within 3 working days of first becoming aware that a defect may exist. The applicant that elects to submit a 3-day field alert report electronically through the SRP must also submit the report via telephone or other telecommunications means and in paper form to the FDA district office or local resident post. Reports of serious, unexpected ADEs are submitted as 15-day alert or “expedited” reports. These reports must be submitted on Form FDA 1932 to the FDA by the applicant within 15 working days of first receiving the information (21 CFR 514.80(b)(2) ). Follow-up reports are submitted on Form FDA 1932 by the applicant if significant new information is revealed during its investigation of adverse drug events that are the subject of 15-day alert reports (21 CFR 514.80(b)(3) ). Periodic reports contain ADE or product defect reports, based on the criteria in 21 CFR 514.80 (b)(4)(iv), and contain “expected” signs already on the label of the product, or are product defects not expected to result in serious adverse events. Periodic reports are submitted on Form FDA 2301 by the applicant at periodic intervals defined by regulation (21 CFR 514.80(b)(4) ).

Approved versus Unapproved Drugs

ADE submission is required by regulation only from companies marketing FDA-approved and conditionally approved animal drugs. Currently there are no regulatory requirements for submitting ADEs for unapproved animal drugs (animal drugs that have not gone through the FDA’s approval process) or for 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 NADA number on the label, or a C-NADA number for conditionally approved animal drugs, although these identifiers on labeling are not currently required by regulation. Information about indexing, conditional approval, and designation of drugs intended for minor uses in major species or for use in minor species can be obtained from CVM’s Office of Minor Use and Minor Species (FDA, CVM (d), 2012). In addition, detailed information about the FDA’s animal drug approval process can be found on CVM’s website (FDA, CVM (e), 2011). Veterinarians and consumers may submit ADE reports involving unapproved drugs; these reports are included in CVM’s ADE database.

Medication Errors

The National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) defines a medication error as

Of these, prescribing errors have been documented to cause the most harm in human patients (Strom and Kimmel, 2006). CVM has received reports of preventable medication errors in animals that may cause unnecessary harm and injury. Medication errors can occur in several settings, including veterinary clinics and hospitals, universities, and human and veterinary pharmacies. Evaluation of ADE reports involving medication errors aids CVM in determining the frequency and severity of medication errors in animals. The information collected in these reports also helps CVM develop educational and outreach materials in an effort to prevent medication errors in animals.

Unclear medical abbreviations are among the most common causes of medication errors. Not all practitioners interpret abbreviations uniformly, and therefore the intended meaning is not always conveyed. This can occur with both written and typed prescriptions. Pharmacists may be unfamiliar with some of the medical abbreviations commonly taught in veterinary school. For example, the abbreviation “SID” (once daily) used on animal drug prescriptions is not recognized by most pharmacies and may be interpreted as “BID” (twice daily) or even “QID” (four times daily), resulting in drug overdoses for animal patients (FDA, CVM (f), 2010). CVM has received several reports of medication errors of this type. Other commonly misinterpreted abbreviations include the use of “U” for units (“U” misread as zero) and the use of “µg” or “mcg” for microgram (mistaken for “mg”). Another common cause of medication errors is the use of trailing zeros and not using leading zeros when writing doses in medical records or on prescriptions. For example, a “5 mg” dose written with the trailing zero as “5.0 mg” can easily be misread as “50 mg.” Similarly, a “0.5 mg” dose written without the leading zero as “.5 mg” can be mistaken for “5 mg.” The FDA has worked to increase the safe use of drug products by minimizing user errors attributed to unclear nomenclature, labels, labeling, and packaging design of drug products. Both premarket and postmarket divisions within CVM review proposed trade names, labels, and packaging and dosing devices during the preapproval process to identify any potential problems. For example, dosing syringes may not be calibrated properly or readily legible, so CVM may recommend changes in the proposed design of these devices to help prevent medication errors after the product is marketed. Sometimes problems may not become evident until after the product has been marketed for some time. Adverse events associated with moxidectin-related overdoses in horses were found to be related to slippage of a syringe locking mechanism during administration of an approved moxidectin product. Several adverse event reports were received regarding this problem, and as a result CVM worked with the sponsor to produce an improved syringe lock (Hampshire et al, 2004).

Reporting Adverse Experiences for Animal Devices

The Federal Food, Drug, and Cosmetic Act [Section 201(h), (21 USC 321 (h) )] defines a medical device as

The FDA does not currently require premarket approval for devices intended for use in animals (e.g., suture material, certain types of bandage materials, intravenous catheters, anesthetic machines, imaging equipment). It is the responsibility of the manufacturer and/or distributor of these articles to ensure that they are safe, effective, and properly labeled. The FDA does have regulatory oversight over veterinary devices and can take appropriate regulatory action if a device is misbranded, mislabeled, or adulterated. Although not required by regulation, manufacturers and distributors of veterinary devices may submit reports of adverse events associated with marketed devices. Most adverse event reports that CVM receives for animal devices come directly from veterinarians or animal owners.