ecent guidance on safety monitoring/surveillance in the US and EU indicates a shift in focus toward aggregate safety assessments and scientific evaluation of integrated safety data. Expectations are for a more systematic approach to identify and characterize important safety information. For clinical trial safety monitoring, aligned with CIOMS VI: Management of Safety Information from Clinical Trials (2005), the FDA has issued the IND Safety Reporting final rule.

Sponsors should have a systematic approach to safety surveillance to comply with safety reporting requirements and to improve the overall quality of safety reporting.

FDA has issued the below, proclaiming: An effective systematic approach by sponsors to safety surveillance, coupled with limiting the scope of IND safety reports to FDA … to suspected adverse reactions that are both serious and unexpected, allows all parties to focus on important safety issues and take actions needed to minimize the risks of participation in a clinical trial.

• Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans (2010 Final Rule)
• Sponsor Responsibilities — Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies (2025 Guidance for Industry)

FDA expects this approach to substantially reduce the number of reports containing nonmeaningful safety information.

The FDA Development Safety Update Report (DSUR) is a tool for FDA and sponsors, partnered together, to identify and manage potential risks and to reduce exposure of study participants to unnecessary risks.

FDA is now permitting the use of an ICH E2F-compliant DSUR—a more comprehensive and informative update report—in lieu of the IND annual report under 21 CFR 312.33: E2F Development Safety Update Report (2011 Guidance for Industry)

The FDA DSUR expands the scope of the annual update to include comprehensive information from clinical investigations conducted anywhere in the world and a description of all actions relevant to the safety of the drug by any regulatory authority or by the sponsor, including:

• Providing an update on the status of the clinical development program and study results
• Summarizing current understanding and management of identified and potential risks
• Describing new safety findings that could have an impact on the protection of study participants
• Examining whether information obtained during the reporting period aligns with prior knowledge about the safety of the investigational drug.

The FDA DSUR, with its comprehensive and detailed safety summary, will enable FDA to more deliberately identify and review new safety signal information and, by better harmonizing annual reporting of clinical trials, will provide consolidated safety information and create a more efficient reporting process to regulatory authorities worldwide.

Meaningful understanding of the evolving safety profile of an investigational new drug (needed for IND safety reporting) requires a periodic analysis of all available safety information (through structured aggregate assessments like the DSUR).

Integrated analysis and a summary of overall safety risks would help increase the usefulness of the safety data and help facilitate efforts to expeditiously identify and assess important safety risks. The overall safety assessment (in the DSUR) is a concise, integrated evaluation of all new clinical, nonclinical, and epidemiological safety information obtained by the sponsor during the reporting period relative to previous knowledge of the drug. It is not intended to require a repeat of information presented in previous sections; however, it does require interpretation of the information and its implications for the IND, and an explanation of how safety information obtained during the reporting period integrates with what was already known about the drug.

Importantly, safety data tabulations should include (among other things) serious suspected adverse reactions. The Reference Safety Information (RSI) listed in the Investigator’s Brochure (IB) forms the basis for expectedness assessments of all “suspected” serious adverse reactions that occur in clinical trials. (Note: The RSI requires aggregate assessments based on sponsor causality determinations.) For suspected serious adverse reactions, those that are unexpected (SUSARs: Suspected Unexpected Serious Adverse Reactions) should be identified.

This is where differences between the FDA DSUR and the ICH E2F DSUR remain. Differences in terminology in safety reporting standards will likely result in different information. For example, FDA uses “reasonable possibility” (2010 Final Rule and 2025 Guidance for Industry) to mean that there is evidence to suggest a causal relationship between the drug and the adverse event. And, while sponsors should consider the investigator’s assessment, they should only submit an IND safety report for events where the sponsor determines that there is a reasonable possibility that the drug caused the event. EU regulators prefer to receive all individual SUSAR reports from sponsors (judged by sponsor and/or investigator): Regulators are concerned that sponsors might miss a signal, that they themselves might miss a signal, and that a signal might slip through the collective efforts of both groups.

The prospective development of a plan for assessing SAEs that are only interpretable in the aggregate is an important component of IND safety reporting (2010 Final Rule and 2025 Guidance for Industry).

In 2017, the Clinical Trial Facilitation Group (CTFG) issued the RSI Q&A. Although aggregate safety analysis is described on a high level as a requirement for determination of expected serious events, it is not a specific topic in the CTFG guidance. No consideration regarding methodologies or processes is made. FDA’s IND safety reporting guidance documents, while not as focused on the RSI, are more comprehensive with regard to aggregate assessment. Few events can be judged to be drug-related based on one or a small number of occurrences.

Aggregate analyses are needed (1) for anticipated SAEs where it would be difficult or impossible to make a causal determination based on a single case or a small cluster; or (2) for suspected expected serious adverse reactions that must be reported if there is a clinically important increase in the rate over that described in the IB (2010 Final Rule and 2025 Guidance for Industry). The FDA has thrown down the gauntlet for anticipated events: a reporting decision for an anticipated event in the study population requires an aggregate analysis. However, the need for aggregate analysis of an already recognized serious adverse reaction has been previously obliged by ICH guidelines. According to ICH E2A: Clinical Safety Data Management (1995), a clinically important increase in the rate of an expected serious adverse drug reaction is subject to expedited reporting. Although this requires an aggregate analysis, how to make aggregate safety assessments in ongoing studies (especially without unblinding study personnel) has not been described in ICH guidance (beyond some high-level principles). The technical details have been left for the sponsors.

Sponsors should have a systematic approach to safety surveillance where an aggregate analysis of specific events could indicate whether those events occur more frequently in the drug treatment group than in a concurrent or historical control group. After each review of accumulating safety data collected across completed and ongoing studies in the program, the sponsor should make a judgment about the likelihood that the drug caused any SAEs.

The US FDA has placed responsibility squarely on sponsors to send a safety report only after they have judged there to be a reasonable possibility that the study drug caused the event. For the EU (and other regional regulatory agencies), assessment of causality considers the opinion of the investigator as well as the sponsor, and all individual SUSARs are required to be reported in an expedited manner. Consequently, it can be challenging to apply a single global approach to report handling. Regulators in different regions could be examining different SUSAR data as trials progress, which can introduce additional challenges.

Interdisciplinary Safety Evaluation for Learning and Decision-Making

Sponsors and the FDA have been working together to improve approaches for assessing accumulating safety data in ongoing programs. The FDA has revised and clarified IND safety reporting requirements to improve the overall quality of safety monitoring and reporting of human drug and biological products, strengthening the agency’s ability to review critical safety information. Additionally, the FDA has revised the definitions and reporting standards to be as consistent as possible with international definitions and standards, in an effort to harmonize safety reporting internationally.

Crucially, the FDA has identified an important new concept in these anticipated events that has compelled us to reimagine how we do interdisciplinary safety evaluation for learning and decision-making. It has forced us to recognize our need for a distinct framework for safety assessments; a framework different from the one that we had been implicitly operating under, which was designed for efficacy analyses. A Framework for Safety Evaluation Throughout the Product Development Life‑Cycle is described by Ball et al. (2019), which sets the foundation for How Aggregate Safety Assessment Planning Supports Investigational New Drug Safety Reporting Decisions that is described by Hendrickson et al. (2024), which provides the safety strategy for Evidence-Based Safety Assessment Using the Bradford Hill Criteria that is described by Loos et al. (2026).

To meet the spirit of the final rule, sponsors have responded by developing processes and tools to evaluate, assess, and act on accumulating safety information during development on an ongoing basis. Now that sponsors and the FDA have aligned with solutions for the final rule, other regulatory agencies—which have had the same concerns as sponsors—will hopefully be realigning about safety reporting.

What reason remains for continuing to avoid this issue raised by the FDA? What’s holding us back now that sponsors have developed solutions for IND safety reporting that improve safety reporting for events requiring an aggregate analysis? All regulatory regions should recognize anticipated events (as well as expected serious events) and provide guidance on how to make aggregate safety assessments in ongoing studies.

To conclude, an inspirational quote from Maya Angelou: Do the best you can. And when you know better, do better.