DSUR, PSUR, PBRER and PADER: which periodic safety report, when, and to whom

A PADER, or periodic adverse drug experience report, is the postmarketing safety report FDA requires under 21 CFR 314.80(c)(2) for each approved drug application: quarterly for three years after US approval, then annually. The DSUR is the annual safety report for a drug still in clinical development, written to ICH E2F. The PSUR and the PBRER are periodic reports for a marketed product. ICH replaced the PSUR format with the PBRER in 2012, but the EU still calls its PBRER-format report a PSUR, and FDA accepts a PBRER in place of a PADER under a waiver.

All four are aggregate reports in pharmacovigilance: each reviews cumulative safety data at a fixed interval, where an individual case safety report (ICSR) carries one case. Urgent findings travel separately. In the US they go as 15-day Alert reports for a marketed drug and as IND safety reports under an investigational new drug application (IND). In the EU they go as individual case reports to EudraVigilance and, from trials, as SUSAR reports under Regulation (EU) No 536/2014. ICH E2C(R2) states in section 1.2 that the PBRER is "not intended to be used to provide initial notification of significant new safety information."

DSUR vs PSUR vs PBRER vs PADER: the comparison

Report	DSUR	PSUR (EU)	PBRER	PADER (PAER for biologics)
Lifecycle stage	In clinical development, marketed or not	Marketed in the EU	Marketed, in any ICH region	Marketed in the US
Governing text	ICH E2F	GVP Module VII	ICH E2C(R2)	21 CFR 314.80; 21 CFR 600.80
Clock starts on	Development international birth date (DIBD): first trial authorization anywhere	The EU reference date in the EURD list	International birth date (IBD): first marketing approval anywhere	US approval date of the application
Frequency	Annual	Set by the EURD list or the marketing authorization; standard cycle 6-monthly, then yearly, then 3-yearly	Set by national or regional requirements, for intervals of 6 months or longer	Quarterly for 3 years, then annual
Due	60 days after the data lock point	70 days after the data lock point for intervals up to 12 months; 90 if longer	70 days for 6 or 12 month intervals; 90 if longer	30 days after each quarter; 60 days after each approval anniversary
Purpose	Annual review of whether new safety information is in accord with what was known, and what could affect trial participants	Evaluation of the risk-benefit balance at defined points after authorization	Integrated benefit-risk evaluation for approved indications	Interval narrative, analysis of 15-day Alert reports, and actions taken
Received by	FDA (as the IND annual report), EU and other authorities; ethics committees where required	The EU PSUR repository, for EU assessment	Regulators accepting the ICH format; FDA under a waiver	FDA

What is a PADER?

Every holder of an approved new drug application (NDA) files a PADER. 21 CFR 314.98 applies the same rule to abbreviated applications (ANDAs), so generic drugs are covered too. A holder of a biologics license application (BLA) files the equivalent periodic adverse experience report (PAER) under section 600.80(c)(2), on the same cadence counted from the date the license issued.

Under section 314.80(c)(2)(ii), each PADER contains:

1. A narrative summary and analysis of the information in the report.
2. An analysis of the 15-day Alert reports submitted during the interval, each referenced by patient identification code, adverse reaction term and submission date.
3. A history of actions taken since the last report because of adverse drug experiences, such as labeling changes or studies initiated.
4. An index, a line listing of patient identification codes and adverse reaction terms for the ICSRs in the report.
5. An ICSR for each serious-and-expected or nonserious adverse drug experience not already sent as a 15-day Alert report, submitted to FDA only once.

Section 314.80(c)(2)(iii) sets the boundary. Apart from 15-day Alert reports, periodic reporting does not apply to adverse drug experiences from postmarketing studies, the scientific literature or foreign marketing experience. Serious, unexpected cases from those sources reach FDA as 15-day Alert reports instead, and the PADER analyzes them. From a postmarketing study, a 15-day Alert report is required only when the applicant concludes there is a reasonable possibility that the drug caused the event (section 314.80(e)).

When is a PADER due?

The first quarter begins on the approval date. Each quarterly report is due within 30 days of the quarter's close, and each annual report within 60 days of the approval anniversary. For a drug approved on March 14, 2025:

Report	Interval	Due by
Quarterly PADER 1	March 14 to June 13, 2025	July 13, 2025
Quarterly PADER 12, the last	December 14, 2027 to March 13, 2028	April 12, 2028
First annual PADER	March 14, 2028 to March 13, 2029	May 13, 2029

FDA may reestablish quarterly reporting by written notice, for example after approving a major supplement.

Can a PBRER replace a PADER? The FDA waiver

Yes. FDA's guidance Providing Postmarketing Periodic Safety Reports in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report) (November 2016) sets out when a PBRER can stand in for the PADER, the PAER or the PSUR to meet sections 314.80(c)(2) and 600.80(c)(2). An applicant without a PSUR waiver requests a PBRER waiver under 21 CFR 314.90(a) or 600.90(a), and one letter can cover several applications. An existing PSUR waiver carries over to the PBRER while the data lock point and frequency stay the same.

Four conditions travel with the waiver:

• Nonexpedited ICSRs received in the interval still go to FDA electronically.
• The PBRER carries a list of every ICSR submitted in the interval.
• It carries a narrative of changes to the approved US labeling, with the labeling in effect on the data lock point.
• The US frequency still holds. After year three a report is due every year, so a 3-year PBRER cycle needs an annual PADER, PAER or PSUR in years one and two. In the first three years, an applicant can ask to replace quarterly reports with 6-month or 12-month PBRERs.

A 6-month or 12-month PBRER is due to FDA within 70 calendar days of the data lock point, a longer one within 90.

PSUR vs PBRER: what changed in 2012

The PBRER replaced the PSUR as the ICH periodic report in November 2012, moving its focus from new safety information to an integrated evaluation of benefit and risk. ICH had created the PSUR with its E2C guideline in November 1996 and added an addendum in 2003. The PSUR's focus was new safety information and whether the reference safety information needed to change.

ICH E2C(R2) reached Step 4 on November 15, 2012, and replaced the PSUR with the Periodic Benefit-Risk Evaluation Report. The guideline defines it as a critical analysis of new information on a product's risks and on its benefit in approved indications, leading to an appraisal of the overall benefit-risk profile. Its 20 sections add an overview of new, ongoing and closed signals, a signal and risk evaluation, a benefit evaluation and an integrated benefit-risk analysis. FDA published E2C(R2) as guidance for industry on July 19, 2016.

Why the EU still says PSUR

EMA's PSUR page explains that the EU format is based on the PBRER and has been legally required under Commission Implementing Regulation (EU) No 520/2012 since January 2013. The name PSUR keeps the terminology of EU legislation. Four EU specifics:

• Frequency: the EURD list, legally binding and updated monthly, sets each active substance's frequency, data lock point and submission date, and overrules the standard 6-monthly, yearly, then 3-yearly cycle.
• Submission: every PSUR goes to the central PSUR repository, mandatory since June 13, 2016.
• Assessment: a PSUR single assessment (PSUSA) reviews products with the same active substance together, across marketing authorizations.
• Exemptions: generics, well-established use, homeopathic and traditional herbal products (Articles 10(1), 10a, 14 and 16a of Directive 2001/83/EC) are exempt from routine PSURs unless the marketing authorization or the EURD list requires them.

Medical devices use the same abbreviation for a different report. Under Article 86 of the EU Medical Device Regulation (EU) 2017/745, class IIa, IIb and III device manufacturers prepare a PSUR from their post-market surveillance data. It is updated at least annually for class IIb and III, and at least every two years for class IIa.

DSUR vs PSUR: before approval and after

A DSUR reviews a drug's safety each year while it is in clinical development; a PSUR reviews a marketed product's risk-benefit balance on the schedule the EURD list sets. The DSUR follows the investigational drug, marketed or not, and its first concern is the protection of trial participants. ICH E2F sets a reporting year from the DIBD and submission within 60 calendar days of the data lock point. FDA accepts the DSUR to meet the IND annual report requirement of 21 CFR 312.33. Its sections and routes are in the guide to the development safety update report.

Once a drug is approved and development continues, the DSUR and the PBRER run side by side. ICH E2F (section 2.2) lets the sponsor prepare the DSUR on the IBD so both reports share one data lock point, and E2C(R2) section 2.8.1 says the same. Appendix D of E2C(R2) lists the sections the two can share, among them the cumulative tabulation of serious adverse events from clinical trials, trial findings, literature and conclusions. Each report still stands alone, because each serves a different regulatory purpose.

What every periodic report needs from adverse event data

The four reports differ in audience and cadence but draw on the same event records, and four requirements decide whether those records are ready.

The dictionary version is stated. PBRER section 6.1 names the coding dictionary version, and the trial tabulations present the MedDRA Preferred Term and System Organ Class, so each event needs to carry the version that coded it. In oncology trials each event also carries a CTCAE grade. CTCAE v5.0 (837 terms) is built on MedDRA 20.1 and v6.0 (850 terms) on MedDRA 28.0, so a cumulative tabulation that spans the switch has to state which MedDRA version coded each event; see every CTCAE v6.0 change, term by term. Consistent MedDRA coding for adverse events lets a cumulative table count one event as one event.

Seriousness is settled per term. The clinical trial tabulations in both the DSUR and the PBRER include only the terms that made a case serious, blinded and unblinded. Both guidelines tell sponsors not to unblind data to write the report.

Causality is assessed case by case, and counted in aggregate. E2C(R2) notes that individual causality assessment has less value in aggregate data, where rates can be compared. The trial tabulations therefore include every serious adverse event for the drug, comparators and placebo. At the case level, attribution still decides which cases are expedited. An IND safety report needs a reasonable possibility that the drug caused the event, and so does a 15-day Alert report from a postmarketing study under section 314.80(e).

Expectedness is measured against the label. Section 314.80(a) defines an unexpected adverse drug experience as one not listed in the current labeling, including a more severe or more specific form of a listed event. Hepatic necrosis is unexpected when the label mentions only elevated hepatic enzymes or hepatitis. An adverse reaction attributed correctly during the trial can reach the label at approval. One found after launch reaches the label through a labeling supplement or an FDA-required safety labeling change, and the next PADER records it in its history of actions taken.

An illustrative oncology case

Take an illustrative checkpoint inhibitor in a phase 2 trial. A participant develops serious immune-related hepatitis, the investigator brochure does not list it, and the sponsor judges a reasonable possibility that the drug caused it: the case goes to FDA as an IND safety report, and it is counted in the next DSUR's cumulative tabulation of serious adverse events. After approval, the label lists hepatitis. A spontaneous report of serious hepatic necrosis is then unexpected by greater severity, goes to FDA as a 15-day Alert report, and is analyzed in the next PADER.

Where Burna AI fits

Burna AI works at the site, where the adverse event is first documented. It grades each event in the note against the CTCAE version the protocol names, with its MedDRA Lowest Level Term (LLT) code. It scores attribution against every drug in the regimen with the WHO-UMC and Kramer methods, reasoning shown. Every grade traces to the line in the medical record that produced it, and a qualified investigator signs it under 21 CFR Part 11. The signed record produces FDA MedWatch, IRB and serious adverse event reports, all listed in what Burna AI does today. AI suggests, clinicians decide. Human-in-the-loop, always.

The DSUR, PSUR, PBRER and PADER remain the sponsor's and the applicant's work. What improves is the event data beneath them: attribution at the moment of decision during the trial, and the same engine after approval for postmarket surveillance.

To see an adverse event graded, attributed and MedDRA-coded at the site, with the line in the medical record that produced it attached, book a 15-minute conversation.

Periodic safety report questions

What is the difference between a PSUR and a PBRER?

The PBRER replaced the PSUR under ICH E2C(R2) in 2012, adding signal and risk evaluation and an integrated benefit-risk analysis. The EU still calls its PBRER-format report a PSUR.

Is a PADER required for generic drugs?

Yes. Section 314.98 requires ANDA holders to comply with section 314.80, periodic reports included. In the EU, by contrast, generics are exempt from routine PSURs unless the marketing authorization or the EURD list requires them.

What is the difference between a PADER and a PAER?

The PADER covers drugs approved under an NDA or ANDA (21 CFR 314.80(c)(2)); the PAER covers biologics licensed under a BLA (21 CFR 600.80(c)(2)). The content and the quarterly-then-annual cadence run in parallel.