The FDA’s Development Safety Update Report requirements come from ICH E2F guidance and satisfy the annual IND reporting obligation under 21 CFR 312.33. A sponsor must submit one DSUR per year for each investigational drug or biologic, filed within 60 days of the Data Lock Point, in eCTD format through the Electronic Submissions Gateway, following a 20-section structure with additional U.S.-specific appendices.1U.S. Food and Drug Administration. E2F Development Safety Update Report
What the DSUR Satisfies and What It Replaces
21 CFR 312.33 requires sponsors to submit a progress report within 60 days of the anniversary date the IND went into effect.2eCFR. 21 CFR 312.33 – Annual Reports The regulation itself describes the older IND annual report format. FDA guidance implementing ICH E2F allows a DSUR to satisfy that obligation instead, and this is now the standard format sponsors use.3FDA/ICH Guidance Document. E2F Development Safety Update Report Guidance for Industry
The DSUR is not the same as an expedited IND safety report. IND safety reports under 312.32 cover individual serious adverse events on a fast timeline. The DSUR is annual and cumulative: it pulls together clinical trial data, non-clinical findings, and any post-marketing information from every country where the product is being studied, giving the FDA a full picture of how the safety profile has evolved over the past year.
When the DSUR Is Due
Every DSUR is anchored to the Development International Birth Date, the date a sponsor first received authorization to conduct a clinical trial for the product anywhere in the world.4European Medicines Agency. ICH Guideline E2F: Development Safety Update Report (DSUR) – Step 5 The anniversary of the DIBD sets the Data Lock Point, which is the cutoff for data in the report. For U.S. submissions, the DLP can alternatively be pegged to the anniversary of the date the IND went into effect, since U.S. clinical development sometimes begins before or after the first global authorization.5ICH Database. Overview of ICH E2F – Development Safety Update Report (DSUR)
Once the DLP passes, the sponsor has 60 calendar days to finalize and submit.2eCFR. 21 CFR 312.33 – Annual Reports Compiling worldwide safety data, running analyses, and drafting the overall safety assessment takes real time. Sponsors who wait until the DLP to begin drafting rarely finish comfortably.
The 20 Required Sections
ICH E2F specifies 20 numbered sections. Not every section applies to every product at every stage, but the structure must be followed even if a section simply states that no relevant information is available.6ICH Database. ICH E2F Example DSUR – Phase III Investigational Drug
- Sections 1–4 cover the introduction, worldwide marketing approval status, actions taken for safety reasons during the period, and changes to reference safety information.
- Sections 5–7 provide the inventory of clinical trials ongoing or completed, estimated cumulative subject exposure (both clinical development and any marketed use), and the line listings and summary tabulations of adverse events.
- Sections 8–13 include significant clinical trial findings, safety data from non-interventional studies, other clinical safety information, marketing experience data, non-clinical data, and relevant literature.
- Sections 14–17 handle cross-references to other DSURs for the same product, lack-of-efficacy data, region-specific information, and any late-breaking information received after the DLP.
- Sections 18–20 contain the overall safety assessment with risk evaluation and benefit-risk considerations, a summary of important risks, and conclusions.
Sections 18 through 20 carry the analytical weight. The overall safety assessment is not a data dump. It requires the sponsor to interpret new and cumulative safety information, identify emerging risks, and evaluate whether the benefit-risk balance still supports continued development. The FDA expects sponsors to flag specific toxicities such as hepatotoxicity, cardiovascular effects (including QT prolongation), bone marrow suppression, renal toxicity, and immunogenicity, rather than burying concerning signals inside dense tabulations.
Reference Safety Information
The DSUR must identify which version of the Investigator’s Brochure serves as the baseline for determining whether an adverse reaction is “expected” or “unexpected.” The rule is straightforward: the IB in effect at the start of the reporting period is the reference document. Section 7.1 must state the version number and date of that IB.
If the IB was revised during the reporting period, the sponsor should attach the updated version and describe what changed in Section 4. Expectedness drives expedited reporting obligations. An adverse reaction listed in the IB at the period’s start won’t trigger an expedited IND safety report, but a newly identified reaction might.
Line Listings and Cumulative Exposure
Section 7 requires line listings of all serious adverse reactions from the sponsor’s clinical trials during the reporting period. These go into an appendix, organized first by trial and then by System Organ Class. Each subject appears only once under the most serious reaction, even if multiple reactions were reported.
The line listings must include both blinded and unblinded data. For blinded trials, the treatment group is listed as “blinded” without breaking the blind. Each entry needs the study ID, subject ID, sponsor case reference number, country, patient demographics, dose and regimen, date of onset, the adverse reaction term using MedDRA Preferred Terms, the outcome, and any relevant comments such as disagreement with the reporter’s causality assessment.
Beyond the interval line listings, the DSUR requires cumulative summary tabulations of all serious adverse events since the DIBD. Sections 6.1 and 6.2 provide cumulative exposure figures for the clinical development program and any marketed use, drawn from every ongoing and completed trial worldwide. When treatment assignments are still blinded, subjects can be estimated based on the randomization ratio. Exposure data gives context to everything else in the report: a handful of adverse reactions in a 50-person Phase 1 trial tells a different story than the same number across 10,000 Phase 3 subjects.
U.S.-Specific Appendix Requirements
The DSUR is an international document, so Section 16 collects region-specific information. For U.S. submissions, the FDA expects several items beyond the core international template:
- Cumulative SAR tabulations broken out by System Organ Class, reaction term, and treatment arm, with unexpected reactions flagged.
- A death list covering subjects who died during the reporting period, with case number, assigned treatment (which may still be blinded), and cause of death.
- A dropout list covering all subjects who dropped out in connection with an adverse event during the period, regardless of whether the event was considered drug-related.
- Significant changes to Phase 1 protocols made during the period that weren’t previously reported as protocol amendments.
- A summary of significant manufacturing or microbiological changes, with a discussion of any potential safety implications.
- A description of the general investigation plan for the coming year, replacing the plan submitted the previous year.
- Optionally, an outstanding business log of pending matters with the FDA for which the sponsor expects a reply or meeting.
These items closely track what the old IND annual report required, so U.S. sponsors familiar with that format will recognize them. The difference is that they now sit within the broader DSUR framework rather than standing alone.
How to Submit
DSURs are submitted electronically in the Electronic Common Technical Document (eCTD) format through the FDA’s Electronic Submissions Gateway. The FDA supports eCTD versions 3.2.2 and 4.0, with version 4.0 available for new IND submissions since September 2024.7U.S. Food and Drug Administration. Electronic Common Technical Document (eCTD)
eCTD submission is mandatory for commercial IND applications and all subsequent reports filed to them. For noncommercial INDs, such as investigator-sponsored or expanded-access INDs, electronic submission is encouraged but optional. The content requirements are the same either way.
Multiple INDs, Co-Development, and CRO Delegation
The FDA expects a single DSUR covering all dosage forms, strengths, indications, and patient populations for a given investigational drug wherever feasible. If the sponsor holds multiple INDs for the same active substance, one DSUR can be cross-referenced to satisfy the annual reporting obligation for each.
When multiple sponsors are involved through co-development or licensing arrangements, they should arrange to submit a single DSUR whenever possible, backed by a written agreement specifying how safety data will be exchanged and who prepares and files the report. If a combined report isn’t feasible, each sponsor can file separately, but the report must explain why.
A sponsor can transfer any or all Part 312 obligations, including DSUR preparation and submission, to a contract research organization. The transfer must be in writing, and if only some obligations are delegated, the agreement must specify which ones.8eCFR. 21 CFR 312.52 – Transfer of Obligations to a Contract Research Organization Any obligation not explicitly covered in the written agreement stays with the sponsor. A CRO that assumes DSUR responsibility faces the same regulatory exposure as the sponsor. The sponsor should confirm the CRO has access to all global safety data needed to compile the report.
What Happens If You Miss or Get It Wrong
Under 21 CFR 312.44, the FDA may propose to terminate an IND at any phase of development if the sponsor fails to submit an accurate annual report in accordance with 312.33.9eCFR. 21 CFR 312.44 – Termination Failure to make any report required under Part 312 is also an independent ground for termination. IND termination halts all clinical trials under that application.
If an IND is placed on inactive status because clinical work has paused, annual reports are not required during the inactive period. But an IND that stays inactive for five or more years can itself be terminated. Sponsors who expect to resume development should keep the IND active and continue filing DSURs, even if there is little new data to report during a gap in trials.
The FDA also uses the DSUR itself as a decision input. After reviewing one, the agency can impose limitations on current or future development, such as capping the maximum dose to be evaluated or requiring specific safety data before pediatric enrollment. If the report reveals that subjects face an unreasonable and significant risk, the FDA can place a clinical hold on one or more studies under 21 CFR 312.42.10eCFR. 21 CFR 312.42 – Clinical Holds and Requests for Modification
When DSUR Reporting Ends
The DSUR covers the investigational phase. Once the FDA approves a product, periodic reporting shifts to a post-marketing format. Under 21 CFR 314.80(c)(2) and 600.80(c)(2), approved products require quarterly periodic safety reports for the first three years after U.S. approval, then annual reports.11Food and Drug Administration. Providing Postmarketing Periodic Safety Reports in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report) Guidance for Industry The traditional format is the Periodic Adverse Drug Experience Report (PADER) or Periodic Adverse Event Report (PAER), though sponsors can request to submit in the ICH E2C(R2) Periodic Benefit-Risk Evaluation Report (PBRER) format instead.
The transition isn’t always clean. A product approved for one use may still have ongoing investigational studies for new indications or populations. In that situation, the sponsor may need to file both post-marketing periodic reports for the approved use and a DSUR covering the continuing investigational program, until all development work concludes.