Post-approval Animal Drug Reporting Requirements
Following approval of a new animal drug, sponsors must submit to CVM reports of adverse drug events, product defects/manufacturing defects, periodic drug experience reports (annually or semi-annually in a specific format), and other submissions and reports as applicable. Many of the post-market reporting requirements are outlined in 21 CFR 514.80. In addition, drug registration and listing is required.
Continuous monitoring of approved New Animal Drug Applications (NADAs) and Abbreviated New Animal Drug Applications (ANADAs) throughout a drug’s lifecycle ensures that FDA’s Center for Veterinary Medicine (CVM) obtains information regarding potential problems with the safety and effectiveness of marketed animal drugs and potential product quality issues/manufacturing problems.
Further detail is provided below.
1. Reports of Adverse Drug Experiences and Product Defects/Manufacturing Defects:
Sponsors of approved animal drugs are required to submit product/manufacturing defect reports and adverse drug event reports (including lack of expected effectiveness). Most reports are required to be submitted electronically. For information on electronic reporting of adverse drug experiences and product defect/manufacturing defects to CVM, see www.fda.gov/IndustryReportAnimalAE.
- Three-day NADA/ANADA field alert reporting: Sponsors must submit reports of product defect/manufacturing defects that may result in serious adverse events within 3 working days of first becoming aware that such a defect may exist. (See 21 CFR 514.80 (b)(1))
- Fifteen-day NADA/ANADA alert report: Sponsors must submit initial reports for serious and unexpected adverse drug events within 15 working days of first receiving the information. (See 21 CFR 514.80 (b)(2)(i))
- Follow-up report: The sponsor must investigate serious and unexpected adverse drug events reported under 15-day NADA/ANADA reports and submit follow-up reports according to specific timelines (See 21 CFR 514.80 (b)(2)(ii)).
- All other adverse drug experience reports and product/manufacturing defect reports (not previously submitted) must be submitted individually to FDA on or before a semi-annual or annual due date, depending on how long the drug has been approved. (See 21 CFR 514.80 (b)(4)(iv))
2. Drug experience reports (DER):
Sponsors of approved animal drugs are required to submit drug experience reports electronically through the eSubmitter or by paper by using the FDA Form 2301. Post approval reporting requirements for submitting drug experience reports include (See the below DER requirements in 21 CFR 514.80(b)(4) and (5)):
- Mailing pieces and other labeling must be submitted at the time of initial dissemination. For prescription drugs, advertisements must also be submitted at the time of initial dissemination.
- After an animal drug is approved, the sponsor is required to submit a semi-annual drug experience report for the first two years and yearly thereafter based on the anniversary date of the original approval of the application.
- The yearly periodic drug experience report must be submitted within 90 days of the anniversary date of the approval of the application and the semi-annual report must be submitted within 30 days.
- In the periodic DER report, the sponsor is required to submit the following for their approved application:
- Sponsor and distributor labels (and labeling components) for animal drug products that are in commercial distribution; including a summary of any changes in labeling made since the last report.
- Distribution data or quantity marketed data on the number of units sold or distributed in and outside the United States (i.e., domestic and export sales) for the reporting time period.
- Certain clinical trials and non-clinical data.
- Summary report of increased frequency of adverse drug experience.
- At the time of initial distribution of a new animal drug product by a distributor, the sponsor must submit a Special DER-New distributor statement. In this submission the sponsor must provide a copy of the distributor's current product labelling which must be identical to the approved labeling except for a different and suitable proprietary name (if used) and the name and address of the distributor. The name and address of the distributor must be preceded by an appropriate qualifying phrase as permitted by the regulations such as “manufactured for” or “distributed by.”
3. Labeling Changes:
After an animal drug is approved, the sponsor is required to notify FDA of any changes to the drug’s labeling. Major revisions in labeling, such as updating information pertaining to effects, dosage, adverse reactions and addition of an intended use, require the submission and approval of a supplemental application prior to distribution of the drug made using the change. Some labeling changes may be placed into effect prior to approval of a supplemental application, e.g., those that increase the assurance of drug safety and minor changes in style and design that do not impact safe use of the drug. (See 21 CFR 514.8(c)(2) &(3))
4. Antimicrobial Reports:
In 2008, Congress amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) to require animal drug sponsors to submit distribution data for antimicrobial drugs for food-producing animals. In 2016, FDA published the Final Rule, “Antimicrobial Animal Drug Sales and Distribution Reporting” which describes the reporting requirements. Sponsors of approved or conditionally approved animal drug products that contain an antimicrobial active ingredient are required to report the number of units sold or distributed in the United States (i.e., domestic sales) for each month on a calendar year basis by March 31st of each year. Sponsors are required to provide species specific sales estimates of the percentage of each product sold or distributed domestically for use in the four major food animal species categories (cattle, swine, chicken and turkey) but only for such species that appear on the approved label. Sponsors are required to submit the reports electronically through the eSubmitter or by paper by using the FDA Form 3744. FDA publishes an annual summary report of the data and information that is received by December 31 of the following year. (See 21 CFR 514.87)
5. Drug listing and Registration:
Owners or operators of drug manufacturing establishments are required to register their establishments with FDA. Registrants are also required to list each drug manufactured at their establishment(s) intended for commercial distribution and submit updated drug listing information to FDA twice each year, in June and December, notifying FDA if this information has changed. Establishment registration and drug listing data are submitted electronically using structured product labeling (SPL) format. To delist, the applicant should go to the FDA’s eLIST system and select, “completed” for the marketing status and enter the marketing end date which is the expiration date of the last lot marketed or exhausted from the distribution warehouse. (See Section 510 of the FD&C Act & 21 CFR Part 207)
6. Chemistry and Manufacturing:
CVM review of the manufacturing information continues throughout the life-cycle of the product, including the manufacturing process of clinical and pilot/production batches before the drug is approved, and any changes that are implemented thereafter. In this way, the Chemistry, Manufacturing and Controls (CMC) technical section helps assure that the quality and characteristics of the drug sold to the public continue to conform to that of the drug determined to be safe and effective prior to approval. After approval, all CMC changes must be reported to CVM in either supplemental applications or minor changes and stability reports (MCSRs) depending on the nature of the change. Significant manufacturing changes cannot be implemented prior to approval of the change by CVM. A sponsor is also required to submit annually, in the MCSR, updated stability data generated on marketed product, according to an approved stability commitment. (See 21 CFR 514.8 & GFI #83 Chemistry, Manufacturing, and Controls Changes to an Approved NADA or ANADA)
7. Voluntary Withdrawal of Approval:
Sponsors can request to voluntarily withdraw the approval of their application if the drug product is no longer marketed. Sponsors are required to submit two paper copies of their request to the Document Control Unit (HFV-199). After the request is approved, notice of the withdrawal of the application will be published in the FEDERAL REGISTER. (See 21 CFR 514.115(d))