Reporting Adverse Product Experiences from Marketed Products

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Chapter: Pharmacovigilance: Legal Basis - United States

The regulations specify two mechanisms for reporting post-marketing adverse product experiences: 15-day alert reports and periodic reports.


The regulations specify two mechanisms for reporting post-marketing adverse product experiences: 15-day alert reports and periodic reports. A 15-Day Alert Report must be submitted by an applicant or licensed manufacturer within 15 days after receiving informa-tion regarding a domestic or foreign ‘serious’ and ‘unexpected’ adverse product experience (21 C.F.R. §§ 310.305(d), 314.80(c)(1)(i), 600.80(c)(1)(i)). A periodic report is submitted for any adverse product experience that is not ‘serious’ and ‘unexpected’ (21 C.F.R. §§ 314.80(c)(2)(i), 314.98, 600.80(c)(2)(i)).

All domestic adverse product experience reports for both drugs and biological products (unless treated differently as discussed above) should include a completed FDA Form 3500A for each individual patient or attached publication. If the adverse product experi-ence is foreign, then either a Form 3500A or a Coun-cil for International Organizations of Medical Sciences (CIOMS) I is acceptable (21 C.F.R. §§ 314.80(f), 600.80(f)). If the product is a vaccine, then a VAERS form should be used (21 C.F.R. § 600.80(f)). Appli-cants or licensed manufacturers may use computer-generated forms or an alternative format, such as a computer-generated tape or tabular listing, if the alternative format contains the same information as Form 3500A and if the appropriate FDA department agrees to the alternate format in advance (Id.).

The FDA has proposed a regulation requiring the reporting of adverse product experiences in electronic format but has not yet taken final action on the matter (63 Fed. Reg. 59,746 (1998)). In the interim, the agency has offered guidance for applicants and licensed manufacturers that wish to file such reports electronically [FDA CDER/CBER Draft Guidance on Providing Regulatory Submissions in Electronic Format – Postmarketing Periodic Adverse Drug Expe-rience Reports (June 2003)].

15-Day Alert Reports

An applicant or licensed manufacturer must submit a ‘15-Day Alert Report’ to FDA within 15 calen-dar days of receiving information of a ‘serious’ and an ‘unexpected’ domestic or foreign adverse product experience (21 C.F.R. §§ 310.305(d), 314.80(c)(1)(i), 600.80(c)(1)(i)).

The definition of ‘serious’ for purposes of report-ing post-marketing adverse product experiences is iden-tical to that for IND adverse product experiences discussed above (21 C.F.R. §§ 310.305(b), 314.80(a), 314.98, 600.80(a)). The definition of ‘unexpected’ for post-marketing adverse product experiences is simi-lar to that for the IND adverse product experiences. An adverse product experience is ‘unexpected’ if the experience is not listed in the current labelling for that product (21 C.F.R. §§ 310.305(b), 314.80(a), 314.98, 600.80(a)). An adverse product experience is ‘unex-pected’ even if it could have been anticipated from the pharmacological properties, of the product so long as it is not listed in the labelling (Id.). This definition includes events that are symptomatically and patho-physiologically related to events listed in the labelling but that differ because of greater severity or specificity (Id.). As an example of an event that is ‘unexpected’ due to greater severity, the regulations cite hepatic necrosis when the labelling refers only to elevated hepatic enzymes or hepatitis and cerebral thromboem-bolism and cerebral vasculitis when the labelling refers only to cerebral vascular accidents (Id.).

Unlike the criteria for expedited reporting of adverse events in investigational drugs, the regula-tions regarding reporting spontaneous post-marketing events do not require an assessment of causality. It is the FDA’s view that when a report regarding a drug is made spontaneously, causality is implied, because the reporter otherwise would not have taken the time to transmit the information to the applicant or to a regulatory authority.

15-Day Alert Report Follow-Ups

Applicants or licensed manufacturers are also required to promptly perform a ‘follow-up’ investigation into the adverse product experience and to separately report any new information to the FDA as a ‘15-Day Alert Report Follow-Up’ within 15 calendar days receiv-ing that information (21 C.F.R. §§ 310.305(c)(2), 314.80(c)(1)(ii), 314.98, 600.80(c)(1)(ii)). If the appli-cant or licensed manufacturer performs an inves-tigation but is unable to uncover any additional information, then the applicant or licensed manu-facturer is expected to maintain a record of the steps taken to seek additional information; however, a follow-up report need not be submitted (Id.).

15-Day Alert Reports Based on Scientific Literature

Fifteen-day alert reports must be filed when ‘serious’ or ‘unexpected’ adverse product experiences are reported in case reports or in the results of formal clinical trials published in scientific or medical jour-nals (21 C.F.R. §§ 314.80(d), 314.98, 600.80(d)). When a 15-day alert report is based on information obtained from an article in a scientific or medical journal, a copy of the article must be included with the report (Id.).

Exceptions to the 15-Day Alert Report Requirements

A 15-day alert report is not required for informa-tion regarding an adverse product experience that was obtained from a post-marketing study, includ-ing a study conducted under an IND applica-tion, unless the applicant or licensed manufacturer concludes that there is a ‘reasonable possibility’ that the product caused the experience (21 C.F.R. §§ 310.305(c)(1)(ii), 314.80(e), 314.98, 600.80(e)). When reports of adverse product experiences obtained during a post-marketing study are reported in any context, they should be marked to indicate that they were so obtained (Id.).


Any post-market adverse product experience that is not ‘serious’ and ‘unexpected’ must be reported to the FDA in a periodic report (21 C.F.R. 314.80(c)(2)(i), 314.98, 600.80(c)(2)(i)). Periodic reports must contain a ‘narrative summary and anal-ysis’ of the information in the report, including an analysis of all 15-day alert reports filed during that period (21 C.F.R. §§ 314.80(c)(2)(ii), 314.98, 600.80(c)(2)(ii)). Periodic reports must also include a completed FDA Form 3500A for each adverse prod-uct experience not reported in a 15-day alert report during the period as well as an index consisting of a line listing of patient identification numbers and adverse reactions terms (Id.). Finally, periodic reports must include a history of actions taken in response to adverse product experiences during the period, such as labelling changes or the initiation of studies (Id.).

Quarterly v. Annual Periodic Reports

During the first 3 years after the date of approval or licensing of a product, periodic reports must be submitted quarterly, beginning on the date of approval of the application (21 C.F.R. §§ 314.80(c)(2)(i), 314.98, 600.80(c)(2)(i)). Each quarterly report must be filed within 30 days of the close of the quarter (Id.). After 3 years, applicants or licensed manufac-turers need only submit annual reports, which must be filed within 60 days of the anniversary of approval or licensing (Id.). The FDA may require an applicant or licensed manufacturer to submit quarterly reports for a period longer than 3 years (Id.).

Follow-Up Investigations for Periodic Reports

Follow-up investigations for adverse product expe-riences that are not ‘serious’ and ‘unexpected’ are not required. If the applicant or licensed manufac-turer chooses to perform an investigation, then it may submit any information that it discovers in the next periodic report rather than filing a sepa-rate ‘follow-up’ report (21 C.F.R. §§ 314.80(c)(2)(i), 314.98, 600.80(c)(2)(i)).

Exceptions to Periodic Reporting Requirements

Periodic reports need not contain adverse prod-uct experience information obtained from reports in scientific literature or from foreign marketing experience or post-marketing studies (including stud-ies conducted under IND applications) (21 C.F.R. 314.80(c)(2)(iii), 314.98, 600.80(c)(2)(iii)). Thus, the only adverse product experiences that must be included in periodic reports are spontaneous reports from domestic sources that have not been included in a 15-day alert report.


In addition to the periodic safety reports that appli-cants must submit to the FDA, annual reports are also required for holders of drug approvals. Although these reports primarily provide ancillary information about the product, such as distribution data and manu-facturing changes, annual reports must also include safety information in the form of copies of unpub-lished reports of new clinical and preclinical findings (21 C.F.R. §§ 314.81(b)(2)).


Applicants and licensed manufacturers are not required to report adverse product experience infor-mation that has already been reported to the FDA. Thus, no report should contain adverse product experiences that occurred in clinical trials if those experiences were previously submitted as part of an approved application (21 C.F.R. §§ 314.80(g), 314.98, 600.80(g)). Similarly, an applicant or licensed manufacturer is not required to file a report if the FDA itself was the source of the adverse product experience information and no additional informa-tion was uncovered during the ‘follow-up’ investiga-tion (21 C.F.R. §§ 310.305(c)(5), 314.80(b), 314.98, 600.80(b)).

Reporting requirements apply to all entities iden-tified on the product’s label as a manufacturer, packer or distributor (21 C.F.R. §§ 310.305(c)(1)(i), 314.80(c)(1)(iii), 314.98, 600.80(c)(1)(iii)). To avoid duplication in reporting, however, these entities may submit any adverse product experience information to the applicant or licensed manufacturer for inclusion in the applicant’s or licensed manufacturer’s 15-day alert report (21 C.F.R. §§ 310.305(c)(3), 314.80(c)(1)(iii), 314.98, 600.80(c)(1)(iii)). This submission must occur within 5 calendar days of the entity’s receipt of the information (Id.). If the entity elects this method, then it must keep a record that includes a copy of each adverse product experience report, the date the report was received, the date that the report was submit-ted to the applicant or licensed manufacturer and the name and address of the applicant or licensed manufacturer (Id.).


The names and addresses of patients should not be included in any reports submitted to the FDA (21 C.F.R. §§ 310.305(e), 314.80(h), 314.81(c)(2), 314.98, 600.80(h)). Instead, the applicant or licensed manufacturer should create a unique code number of less than eight characters for each report (Id.). The applicant or licensed manufacturer must include the name of the person who reported the adverse product experience (Id.). The applicant or licensed manufac-turer also must maintain sufficient patient identifica-tion information to permit the FDA to identify the name and address of individual patients (Id.).


In addition to receiving mandatory adverse event information from drug manufacturers and distributors, the FDA also receives voluntary adverse event reports from the medical community and consumers through its MedWatch programme. This programme provides a system for healthcare professionals and consumers to report adverse events to the FDA with respect to drugs, biologics, medical devices and nutritional products such as medical foods, dietary supplements and infant formulas. Food and Drug Administration’s website permits healthcare professionals to voluntar-ily transmit adverse event information electronically, and the FDA also has designed a specific MedWatch adverse event reporting form that can be submitted by mail or fax. In addition, the FDA has a toll-free telephone number for reporting adverse experiences.

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