Periodic Adverse Drug Experience ReportsCFR 314.80 (C) (2) )

Aggregate reports in pharmacovigilance
Dr.Raghavender Muthyala
Aggregate reports writer
AGGREGATE REPORTS
 Aggregate reporting is the process that reviews the cumulative safety information from a wide range
of sources, on a periodic basis and submit the findings to regulatory authorities worldwide.
 The aggregate safety reports are presented to regulatory authority as soon as the medicine is
marketed anywhere in the world and enables understanding of risk and benefit profile of the product
over period of time.
 Why aggregate reporting is important :
 individual case safety reports were submitted on expedited basis to regulatory authorities, detailed
analysis and evolution of benefit risk ratio of drug is not possible at this level. Therefore periodically
reviewing safety reports received cumulatively worldwide, becomes highly significant to analyse the
benefit risk balance of the product.
Types of aggregate reports:
 1. Pre marketing reports:
 IND Annual reports
 Clinical safety reports
 Development safety update report
 Annual safety reports in Europe
 2. Post marketing reports:
 Periodic Adverse Drug Experience Report (PADER)
 Periodic benefit risk evaluation report(PBRER)/parodic safety update report(PSUR)
 Addendum to clinical overview (ACO)
 NDA and ANDA annual reports
Periodic Adverse Drug Experience Report
What is a PADER?
“Periodic Adverse Drug Experience Report” (PADER/PAER) is a part of post-cumulative
safety reports which need to be submitted to the United States Food and Drug
Administration (USFDA).
Purpose of PADER ?
The main purpose of a “PADER” is to update and evaluate a medicine’s global data and
provide information about drug safety. It provides a brief summary of changing post-
approval information of a drug along with the benefit-risk profile evaluation. This
evaluation provides insights, whether further changes are required for a medicine's labeling
or if additional investigations are required.
What is PADER in regulatory affairs?
A PADER is a type of aggregate safety report required to be submitted by a sponsor or
marketing authorization holder (MAH) to the “US Food and Drug Administration (FDA)”
after obtaining marketing authorization approval.
Frequency of PADER:
“Periodic reports are required for each approved NDA, ANDA, and antibiotic application. Periodic reports are due
quarterly for the first 3 years after approval, and annually thereafter. If marketing is delayed, these reports should
also be submitted quarterly for the first 3 years of marketing”.
Timelines of PADER:
“Periodic reports due quarterly must be submitted within 30 days of the last day of the reporting quarter. Reports
due annually must be submitted each year within 60 days of the anniversary date of approval of the drug”.
What are the FDA regulations in 21CFR 314.80 C )( 2):

FDA regulations in 21 CFR 314.80(c)(2)) require applicants to submit post marketing periodic safety reports in the
PADER format for each approved application.
FDA may extend or reestablish the requirement that an applicant submit quarterly reports or require that the
applicant submit reports under 21 CFR 314.80(c) (2) at different times.
 A periodic report must contain the following four components described below.
Each periodic report is required to contain:
 (1)A narrative summary and analysis of the information in the report;
 The number of non-15-day initial adverse experience reports and the number of non-15-day follow-up reports
contained in this periodic report and the time period covered by the periodic report.
 The number of the 15-day reports submitted during the reporting period. This line listing should include the
manufacturer report number, adverse experience term(s), and the date the 15-day report was sent to the FDA.
 A summary tabulation by body system (e.g., cardiovascular, central nervous system, endocrine, renal) of all
adverse experience terms and counts of occurrences submitted during the reporting period.
 The information should be taken from : 15-day reports submitted to the FDA; non-15-day reports submitted in
the periodic report; reports forwarded to the applicant by the FDA; and-any nonserious, expected adverse
experiences not submitted to the FDA but maintained on file by the applicant. For the adverse experience term
product interaction, the interacting products should be identified in the tabulation.
 Summary of the ADE reports in· which the drug was listed as one of the suspect drugs, but the report was filed
to another NDA or ANDA held by the applicant.
 Listing of the 15-day increased frequency narrative reports of serious, unlabeled events submitted during the
period. This listing should include the adverse event(s) and date sent to FDA.
 For the adverse experience term product interaction, the interacting products should be identified in the
tabulation.
(2) An analysis of the 15-day Alert reports submitted during the reporting interval (all 15-day Alert
reports being appropriately referenced by the applicant's patient identification code, adverse
reaction term(s), and date of submission to FDA);
 This section should include:
 Listing of the 15-day reports of serious, unlabeled experiences submitted during the period. This
listing should include manufacturer control number, adverse event(s), and date sent to FDA.
 Narrative discussion of the clinical significance of the 15-day reports (reports of serious, unlabeled
events and increase in frequency of serious, labeled events). This narrative should assess clinical
significance by type of event, body system, and overall drug safety relating the new information
received during this period to what was already known about the drug.
 The narrative should also state what further actions, if any, the applicant plans to undertake based on
the information gained during the reporting period and include the time period for completing the
actions (i.e., when the applicant plans to start and finish the action and submit the information to the
Agency).
 The narrative discussion should indicate, based on the information learned during the reporting
period, whether the applicant believes either that (1) no change in the product’s current approved
labeling is warranted or (2) there are safety-related issues that need to be addressed in the approved
product labeling.
 If changes in the approved product labeling are under consideration by the FDA, the applicant should
state in the narrative the date and number of the supplemental application submitted to address the
labeling changes
 (3) A history of actions taken since the last report because of adverse drug experiences
(for example, labeling changes or studies initiated)
 A narrative discussion of actions taken must be provided, including any labeling changes and
studies initiated since the last periodic report.
 This section should include:
 A copy of current U.S. product labeling
 A list of any labeling changes made during the reporting period
 A list of studies initiated
 A summary of important foreign regulatory actions (e.g., new warnings, limitations in the
indications and use of the product)
 Any communication of new safety information (e.g., a Dear Doctor letter)
 (4) An index consisting of a line listing of the applicant's patient identification code, and
adverse reaction term(s) for all ICSRs submitted during reporting period. (ICSRs for serious,
expected, and nonserious adverse drug experiences).
 An index line listing of FDA Form 3500As or VAERS forms included in section 4 of the periodic report
must be provided. The line listing for each FDA Form 3500A or VAERS form submitted should
include:
 Manufacturer report number
 Adverse experience term(s)
 Page number of FDA Form 3500A or VAERS form as located in the periodic report
 Identification of interacting products for any product interaction listed as an adverse experience.
 FDA Form 3500As or VAERS forms must be provided for the following spontaneously reported
adverse experiences that occurred in the United States during the reporting period:
 Serious and expected
 Nonserious and unexpected
 Nonserious and expected

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Aggregate reports in pharmacovigilance

What are the FDA regulations in 21CFR 314.80 C )( 2):

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