Examples
Worked examples
- Is an instance
An NDA holder learns that a patient taking its approved drug experienced a serious, unlabeled liver injury; because the event is both serious and unexpected relative to current labeling, the applicant must submit a 15-day Alert report to FDA within 15 calendar days of first receiving that information.
- Is an instance
A manufacturer whose name appears on an approved drug's label as a distributor, but who does not hold the NDA, receives a report of a non-serious adverse event; it may forward that report to the NDA holder within 5 calendar days, and the NDA holder includes it in its next quarterly (or, after 3 years post-approval, annual) periodic report rather than an expedited Alert report.
Counter-examples
Looks similar, but isn't
- Not an instance
A serious, unexpected adverse reaction occurring in a subject enrolled in an ongoing trial of an investigational (not yet approved) drug is reported under IND safety reporting (21 CFR 312.32), not 21 CFR 314.80 — the drug has no approved application yet, so the postmarketing regulation does not apply.
Editorial commentary
21 CFR 314.80 is the FDA regulation requiring holders of an approved New Drug Application or Abbreviated New Drug Application, and any nonapplicant manufacturer named on the label, to report a drug’s postmarketing adverse events to FDA on fixed timelines. It is the legal mechanics underneath the FDA Adverse Event Reporting System (FAERS): FAERS is the database the reports land in, while 21 CFR 314.80 is the rule that creates the reporting obligation itself — who must report, what counts as “serious” and “unexpected,” and the exact deadlines. For research administrators and sponsors, the two are best understood as separate layers of the same system: the database (FAERS) and the regulation that populates it (314.80).
Who must report
The reporting duty falls on the applicant — the holder of an approved New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) — for the drug’s entire marketed life, not just during the approval process. The regulation also reaches nonapplicants: any manufacturer, packer, or distributor whose name appears on the approved product’s label but who does not hold the application. A nonapplicant may satisfy its own obligation by forwarding an adverse drug experience report to the applicant within 5 calendar days of receipt, letting the applicant handle the actual FDA submission, but the underlying duty to surveil for and act on adverse event information applies to both.
What counts as “serious” and “unexpected”
These two terms do specific regulatory work and are not interchangeable with their everyday meanings:
- Serious adverse drug experience — an event resulting in death, a life-threatening experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect, or an event judged serious by the applicant based on appropriate medical judgment even if it doesn’t fit those specific categories (an “important medical event” that could jeopardize the patient or require intervention to prevent one of the outcomes above).
- Life-threatening adverse drug experience — an event that placed the patient at immediate risk of death as it actually occurred, not an event that hypothetically could have been fatal in a more severe form.
- Unexpected adverse drug experience — an event not listed in the drug’s current approved labeling, including one that is more specific or more severe than what the labeling already describes. Expectedness is judged against the label, not against general medical knowledge of the drug class.
An event has to be both serious and unexpected to trigger the fastest reporting track below — a serious-but-labeled event, or an unexpected-but-non-serious event, is instead handled through periodic reporting.
Reporting timelines
21 CFR 314.80 sets three distinct reporting tracks, each with its own clock:
- 15-day Alert reports. Any adverse drug experience that is both serious and unexpected — domestic or foreign — must be reported to FDA as soon as possible, and in no case later than 15 calendar days from the applicant’s initial receipt of the information. If the applicant obtains meaningful new information about a case already reported this way (or FDA specifically requests it), a 15-day follow-up report is required on the same 15-calendar-day clock, run from receipt of the new information.
- Periodic (quarterly) reports. For the first 3 years after a drug’s approval, the applicant must submit periodic reports of all adverse drug experiences not already reported as 15-day Alert reports, on a quarterly basis — due within 30 days of the close of each quarter.
- Annual reports. After that initial 3-year period, periodic reporting drops to an annual cadence, due within 60 days of each anniversary of the drug’s U.S. approval date.
Applicants are also required to maintain written procedures for the ongoing surveillance, receipt, evaluation, and reporting of adverse drug experience information gathered from any source — commercial marketing experience, postmarketing clinical studies, postmarketing epidemiological/surveillance studies, published scientific literature, and unpublished scientific reports — and to retain records of every adverse drug experience known to the applicant, including the underlying raw data, for 10 years.
How this differs from pre-market IND safety reporting
21 CFR 314.80 only applies once a drug has an approved application and is on the market. The analogous obligation for an investigational, not-yet-approved drug still under an active clinical trial protocol is IND safety reporting under 21 CFR 312.32, which governs expedited reporting of suspected unexpected serious adverse reactions (SUSARs) to the FDA and to investigators during the trial itself — see CASRAI’s pharmacovigilance in clinical research guide for how that pre-approval reporting chain works, and the adverse event (AE) entry for the underlying causality-neutral definition these regulations build on. The equivalent postmarketing obligation for biologics (as opposed to drugs approved under an NDA/ANDA) sits in the parallel regulation, 21 CFR 600.80.
Frequently asked questions
Is 21 CFR 314.80 the same thing as FAERS?
No. FAERS is the database FDA maintains to store and analyze adverse event reports; 21 CFR 314.80 is the regulation that legally requires NDA/ANDA holders (and nonapplicant manufacturers/packers/distributors) to submit those reports, and sets the specific timelines and content requirements for doing so. FAERS is also fed by voluntary reports through MedWatch, which are not governed by 314.80’s mandatory reporting timelines.
What is a 15-day Alert report?
It’s the expedited report required for any adverse drug experience that is both serious and unexpected, due within 15 calendar days of the applicant first receiving the information, with a matching 15-day clock for meaningful follow-up information on a case already reported this way.
Does 21 CFR 314.80 apply to investigational drugs still in clinical trials?
No. It applies only after a drug has an approved NDA or ANDA and is on the market. Adverse event reporting for an investigational drug under an active trial protocol is governed instead by IND safety reporting under 21 CFR 312.32.
How long must adverse drug experience records be kept?
Applicants must retain records of all adverse drug experiences known to them, including the underlying raw data, for 10 years.
Machine-readable encodings
Use in your systems
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