Development Safety Update Report (DSUR)

A Development Safety Update Report (DSUR) is the ICH E2F-standardized annual aggregate safety report a sponsor prepares for an investigational product under active clinical development. It summarizes accumulated safety data across every trial in that product’s development program as of a single annual data-lock point (DLP) — distinct from the event-triggered expedited reporting required under 21 CFR 312.32, which reports individual serious unexpected adverse reactions (SUSARs) as they occur rather than the program’s aggregate safety profile over the preceding year.

What makes a report a DSUR

ICH E2F, finalized by the International Council for Harmonisation in 2010, defines the DSUR’s purpose, structure, and timing. A report qualifies as a DSUR if it:

• Covers the whole development program, not one trial. A single DSUR aggregates safety data across all ongoing clinical trials of an investigational product, wherever in the world they are running, rather than being filed per-protocol.
• Is anchored to a Development International Birth Date (DIBD). The DIBD is the date of the product’s first authorization to conduct a clinical trial anywhere, and it fixes the annual reporting cycle — most sponsors use a data-lock point one year after the DIBD (or the prior DLP) as the report’s cutoff.
• Is periodic, not event-triggered. It is due on a fixed annual schedule regardless of whether any individual safety event occurred during the period, unlike expedited SUSAR reporting, which is triggered only by a qualifying event.
• Is a critical analysis, not just a data listing. Beyond tabulating cases, the DSUR requires the sponsor’s own evaluation of the evolving benefit-risk profile — new safety signals, changes to the risk-benefit assessment, and actions taken as a result.

DSUR vs. IND annual report vs. expedited SUSAR reporting

These three obligations are easy to conflate because they all sit under the umbrella of IND safety reporting, but they answer different questions on different clocks:

• Expedited IND safety reporting (21 CFR 312.32) answers “did something serious, unexpected, and possibly related just happen?” A qualifying SUSAR must be reported to FDA within 7 calendar days (fatal/life-threatening, with a complete follow-up report due within an additional 8 days) or 15 calendar days (other SUSARs) of the sponsor’s awareness.
• The IND annual report (21 CFR 312.33) answers “what is the overall state of this IND a year in?” It is a US-specific progress report due within 60 days of the IND’s anniversary date, and its required content overlaps substantially with a DSUR’s.
• The DSUR (ICH E2F) answers “what does this product’s accumulated safety profile look like across its whole development program this year?” It is the internationally harmonized annual aggregate format, due within 60 calendar days of its own data-lock point.

Because the DSUR and the IND annual report serve overlapping purposes, FDA guidance allows a properly prepared DSUR to satisfy the 312.33 annual report requirement in place of a separately formatted US progress report, so long as it addresses the additional US-specific elements 312.33 calls for (such as a general investigational plan for the coming year). Sponsors running trials in both ICH and non-ICH regions commonly use this to avoid preparing two separate annual documents. Note that FDA published a proposed rule in December 2022 that would go further and formally replace the current 312.33 format with the DSUR itself; as of this writing that rulemaking has not been finalized, so the DSUR-in-place-of-312.33 approach remains an option sponsors elect rather than a mandated format.

Standard DSUR structure under ICH E2F

ICH E2F specifies a consistent section order so that regulators reviewing DSURs from different sponsors can find the same information in the same place. Core sections include an introduction, a worldwide marketing-approval status summary, actions taken for safety reasons during the reporting period, changes to the reference safety information, an estimate of subject exposure, a summary of serious adverse events from clinical trials and other sources (including significant findings from non-interventional studies, literature, and other DSURs for the same product), a discussion of any regional regulatory authority or IRB/ethics committee requests, an overall safety assessment, and a conclusion addressing whether the product’s benefit-risk profile still supports its continued development.

Worked examples

• Single DSUR covering multiple trials: a sponsor running three concurrent Phase 2 trials of the same investigational compound compiles one DSUR covering all three, anchored to a single DIBD, summarizing cumulative safety data from the preceding 12-month reporting period rather than filing three separate trial-level safety summaries.
• DSUR satisfying the US annual report: a sponsor submits its DSUR to FDA within 60 calendar days of its data-lock point and includes the additional information 312.33 requires (such as the coming year’s investigational plan), so the single filing satisfies both the ICH E2F obligation and the IND annual report requirement rather than requiring a second, separately formatted document.

Counter-example

An investigator reports a hospitalization for acute liver injury that is assessed as possibly related to the investigational product and is not listed in the current Investigator’s Brochure. Because this event is serious, unexpected, and suspected of a causal relationship, it is a SUSAR reported through the expedited 21 CFR 312.32 pathway within days of the sponsor becoming aware of it — it is not, itself, a DSUR. That same event will later be summarized and analyzed in aggregate within the next scheduled DSUR, but the expedited notification and the annual DSUR are separate obligations on separate clocks, and filing one does not substitute for the other.

Why the distinction matters operationally

Conflating DSUR with expedited IND safety reporting leads to two common operational mistakes: treating the annual DSUR as satisfying an urgent SUSAR notification obligation (it does not — a DSUR due months from now cannot substitute for a 7- or 15-day expedited report owed now), or treating each individual expedited SUSAR report as having discharged the sponsor’s separate annual aggregate-analysis obligation (it has not — the DSUR’s benefit-risk synthesis across the whole reporting period is a distinct regulatory deliverable). Keeping the two pathways and their clocks clearly separated in a trial’s safety management plan is what keeps a sponsor compliant on both fronts.

For the fuller mechanics of AE/SAE/SUSAR classification and the expedited reporting pathway that feeds into a DSUR, see the related guide: Pharmacovigilance in Clinical Research: AE, SAE, and SUSAR Reporting. See also Adverse Event (AE) and Good Pharmacovigilance Practices (GVP).

References

• ICH E2F, “Development Safety Update Report” (2010) — ich.org efficacy guidelines
• 21 CFR 312.33 — IND annual reports
• 21 CFR 312.32 — IND safety reporting (expedited)
• FDA, “E2F Development Safety Update Report” guidance for industry (2011)