FDA adverse event reporting requirements for marketed drugs and biologics

After approval, FDA adverse event reporting is a pair of duties in the Code of Federal Regulations. For a drug with an approved application, the section is 21 CFR 314.80. For a licensed biological product, the section is 21 CFR 600.80. Both require a review of what comes in, a fast report when the experience is serious and unexpected, a periodic report for the rest, and an electronic file FDA can archive.

Those electronic files go to the FDA Adverse Event Monitoring System (AEMS), formerly the FDA Adverse Event Reporting System (FAERS). The AEMS electronic submissions page is where FDA describes that path. This page stays with the regulations. It does not invent rates, case counts, or a vendor preference.

Who must report

Under 21 CFR 314.80, each applicant that has an approved application under 21 CFR 314.50, or an effective approved 505(b)(2) application, must promptly review all adverse drug experience information the applicant obtains or otherwise receives, from any source, foreign or domestic. The sources named in the regulation include commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological and surveillance studies, reports in the scientific literature, and unpublished scientific papers. Any person subject to the reporting requirements must also have written procedures for surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA.

The 15 calendar day alert is not only the applicant’s job. 21 CFR 314.80(c)(1)(iii) applies that alert, and the followup to it, to any person other than the applicant whose name appears on the label as a manufacturer, packer, or distributor. The regulation calls that person a nonapplicant. To avoid duplicate reports to FDA, the nonapplicant may send each report of a serious adverse drug experience to the applicant within 5 calendar days of the nonapplicant’s initial receipt, and keep a record of the report, both dates, and the applicant’s name and address. The applicant then reports under the section.

For biologics, 21 CFR 600.80 puts the review and the reports on any person who has a biologics license under 21 CFR 601.20. The alert also reaches any person whose name appears on the label as a manufacturer, packer, distributor, shared manufacturer, joint manufacturer, or other participant in divided manufacturing. That person may meet the duty by sending serious adverse experience reports to the applicant of the final product within 5 calendar days of receipt, and must keep the same kind of record. Whole blood and blood components, and in vitro diagnostic products, are exempt from 21 CFR 600.80. The regulation says those diagnostics follow device reporting rules.

A report submitted under either section is not, by itself, an admission that the product caused the effect. Both regulations say the applicant need not admit causation, and may deny it. FDA’s release of the report is under the same disclaimer.

Alert reports due within 15 calendar days

21 CFR 314.80(c)(1)(i) requires the applicant to report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but no later than 15 calendar days from initial receipt of the information by the applicant. 21 CFR 600.80(c)(1)(i) states the same clock for each adverse experience with a licensed biological product that is both serious and unexpected.

Serious, in both sections, means an experience occurring at any dose that results in death, a life threatening experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect. An important medical event can also be serious when medical judgment says it may jeopardize the patient and may require intervention to prevent one of those outcomes. Life threatening, in both sections, means the initial reporter’s view that the patient was at immediate risk of death from the experience as it occurred. It does not mean that a more severe form might have caused death.

Unexpected means the experience is not listed in the current labeling. Both sections say an event can be unexpected when it is related to a labeled event but is more severe or more specific. The example in both regulations: hepatic necrosis is unexpected if the labeling only refers to elevated hepatic enzymes or hepatitis.

The applicant must promptly investigate alert reports and submit followup within 15 calendar days of receipt of new information, or as FDA requests. If more information cannot be obtained, the regulation says records should be kept of the unsuccessful steps taken to seek it.

Two limits are easy to miss. A 15 calendar day alert based on the scientific literature must be accompanied by a copy of the published article, and that literature rule applies only to case reports or formal clinical trials in scientific and medical journals. An experience from a postmarketing study is a 15 calendar day alert only when the applicant concludes there is a reasonable possibility that the drug or biological product caused it. Periodic reporting, except for information about the alert reports themselves, does not apply to postmarketing studies, scientific literature, or foreign marketing experience.

Periodic reports

Everything that was not submitted as a 15 calendar day alert still has a periodic home. People often call the drug report a PADER, short for periodic adverse drug experience report. The regulation’s own name is periodic adverse drug experience report. For biologics, 21 CFR 600.80 calls it a periodic adverse experience report.

Under 21 CFR 314.80(c)(2), the applicant reports each such experience at quarterly intervals for 3 years from the date of approval, then at annual intervals. Each quarterly report is due within 30 days of the close of the quarter. The first quarter begins on the approval date. Each annual report is due within 60 days of the anniversary of approval. FDA may, on written notice, extend or reestablish quarterly reporting, or set different times. Followup on an experience that went into a periodic report may go in the next periodic report.

21 CFR 600.80(c)(2) uses the same quarterly then annual pattern, counted from issuance of the biologics license, with the same 30 day and 60 day due dates.

Each periodic report must contain a narrative summary and analysis, an analysis of the alert reports submitted during the interval, a history of actions taken since the last report because of adverse experiences (labeling changes or studies initiated are the examples in the text), an index line listing, and an ICSR for each experience that was not already submitted as an alert. Those ICSRs are the serious expected experiences and the nonserious experiences. They are submitted once. The AEMS page describes the periodic safety report as a descriptive portion plus the ICSRs from the interval that were not submitted as alerts, and it points at 21 CFR 314.80(c)(2) and 21 CFR 600.80(c)(2). The descriptive portion uses eCTD. The ICSRs go electronically to ESG NextGen or the Safety Reporting Portal, on or before the periodic report due date. FDA says not to send again any ICSR that was already submitted.

A periodic benefit risk evaluation report, a PSUR, or a DSUR is a different document from the US periodic report described here. How those aggregate reports differ is covered on the aggregate reports page. This page does not state a waiver that would replace the US periodic report. That question needs the FDA source that grants it.

What the ICSR has to contain

Teams often talk about four elements that make a case valid: an identifiable reporter, an identifiable patient, a suspect product, and an adverse event. 21 CFR 314.80(f) and 21 CFR 600.80(f) do not use the phrase “four elements.” They do require the ICSR to include information in those groups, plus information about the applicant.

For a drug, and for a biological product that is not a vaccine, the regulation lists:

• Patient. An identification code, age at the time of the experience or date of birth, gender, and weight. For nonvaccine biological products the patient is coded. The applicant does not put the patient’s name and address in the report.
• Experience. Outcome, the date of the experience, the date of the report, a description that includes a concise medical narrative, the adverse terms, relevant tests with dates and laboratory data, and other relevant history, including preexisting conditions.
• Suspect product. Name, dose, frequency, and route, therapy dates, the diagnosis for use, whether the product is a prescription or nonprescription product, whether it is a combination product, whether the experience abated after the product stopped or the dose was reduced, whether it reappeared after reintroduction, lot number, expiration date, the National Drug Code or other unique identifier, and concomitant products with therapy dates.
• Initial reporter. Name, address, and telephone number, whether the reporter is a health care professional, and occupation if so. If the reporter is the patient, the reporter’s name is still included.
• Applicant. Name and contact office, telephone, report source (spontaneous, literature, or study are the examples), the date the applicant received the report, application number and type, whether the ICSR is an alert, whether it is an initial report or a followup, and a unique case identification number that stays the same on later followup reports.

Vaccine ICSRs under 21 CFR 600.80(g) add vaccination details, facility information, and a different patient identification rule. Read that paragraph on its own before you copy a drug form onto a vaccine.

The alert clock in both regulations runs from initial receipt of the information by the applicant. The content list is what the submitted ICSR includes. Your procedure should say who decides the report is complete enough to submit, and should keep the receipt date even while a field is still thin. An AE and SAE intake form is where that receipt date and the reporter’s words should land.

Followup and recordkeeping

Followup on an alert is due within 15 calendar days of new information, as described above. Applicants are not required to resubmit adverse experience reports that FDA forwarded to them. They must submit all followup information on those reports.

The applicant must keep, for 10 years, records of all adverse drug experiences or adverse experiences known to the applicant, including raw data and any correspondence. 21 CFR 314.80(k) says FDA may withdraw approval if the applicant fails to establish and maintain the records and make the reports. 21 CFR 600.80(l) says FDA may revoke the biologics license under 21 CFR 601.5 for the same kind of failure.

Safety report submissions, including ICSRs, attachments, and the descriptive part of periodic reports, must be in an electronic format FDA can process, review, and archive. That is 21 CFR 314.80(g)(1) and 21 CFR 600.80(h)(1). A temporary waiver is available on a limited basis for good cause shown, by written request. FDA says it will issue guidance on how to request one.

IND safety reporting and postmarketing

Investigational reporting is a different section from 21 CFR 314.80 and 21 CFR 600.80. A serious unexpected suspected adverse reaction in a trial is the subject of the SUSAR reporting guide on this site. The marketed product rules on this page use labeling as the reference for unexpected, and they start from approval or licensure. The trial rules use the investigator brochure and a sponsor receipt clock that this page does not restate.

The handoff between a sponsor and a partner belongs in the agreement. The pharmacovigilance agreement page is the place on this site for that split. The agreement does not erase the applicant’s duty under 21 CFR 314.80 or 21 CFR 600.80.

Where the electronic file goes, once you are the applicant, is AEMS, formerly FAERS. Beginning 1 October 2026, postmarketing ICSRs sent through ESG NextGen must use E2B(R3). The AEMS page says companies that submit through the Safety Reporting Portal do not have an action item from that particular change. How to choose a path is part of the FAERS and AEMS guide.