FDA guidance "Sponsor Responsibilities - Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies"

Earlier this month, FDA issued its guidance "Sponsor Responsibilities - Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies". As an clinical trialist, the updated FDA guidance (or the 2025 guidance) represents a major step forward, primarily by refining the focus on safety assessment and introducing key operational elements.

The 2025 guidance is not a complete rewrite of the 2012 version ("Safety Reporting Requirements for INDs and BA/BE Studies"), but rather a merger of the 2012 guidance content with the principles from the 2015 draft guidance on safety assessment.

Here is a comparison highlighting the key new elements the sponsor must now consider:

Key New Elements in the 2025 Guidance

The most significant change is a shift from focusing solely on individual case safety reports (ICSRs) to a greater emphasis on proactive, systematic safety assessment and the analysis of aggregate data.

New Concept	Description and Implication for Trialists	Relevant Section in New Guidance
Focus on Sponsor Responsibilities Only	The new guidance is strictly limited to Sponsor Responsibilities for safety reporting. All recommendations for Investigator Responsibilities found in the 2012 guidance have been moved to a separate document, reflecting a clear split in regulatory oversight.	Section I, II (Preamble)
Aggregate Data Assessment	This is the central update. The guidance expands significantly on the requirement to perform regular, proactive aggregate analyses of all accumulating safety data. The goal is to identify new or increased risks that would trigger expedited reporting, rather than relying only on individual case reports.	Section III (Definitions) and Section IV (Aggregate Analyses)
Mandatory Safety Surveillance Plan (SSP)	The guidance introduces the term Safety Surveillance Plan (SSP) as a systematic and organized approach to safety monitoring. The plan should include: 1) Clearly defined roles and responsibilities; 2) A plan for the regular review and evaluation of Serious Adverse Events (SAEs); and 3) The process for performing aggregate safety reviews.	Section IV.C (Safety Surveillance Plan)
Sole Sponsor Causality Determination	The guidance emphasizes that the final responsibility for determining whether an event meets the criteria for expedited reporting (i.e., a "Suspected Adverse Reaction," or SUSAR) lies solely with the sponsor. While the sponsor should consider the investigator's opinion, the sponsor is imputed with the ultimate responsibility for the causality judgment for regulatory submission purposes.	Section III.B (Suspected Adverse Reaction)
Flexibility in Safety Review	The new guidance offers greater flexibility by allowing sponsors to choose which individual, group, or entity (e.g., Safety Monitoring Committee, Data Monitoring Committee) is responsible for reviewing, analyzing, and making decisions regarding IND safety reporting.	Section IV.C.1 (Features and Composition of the Entity)

This shift aims to reduce the "noise" of over-reporting uninformative individual adverse events, which was a concern under the old paradigm. Instead, the focus is placed on the sponsor's expert medical review and comprehensive analysis of the overall safety data package.

Here is a side-by-side comparison table summarizing the main discussion points and key changes between the 2012 and 2025 FDA guidance documents on safety reporting.

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Safety Reporting Guidance: 2012 vs. 2025 Comparison

Discussion Point	2012 Final Guidance: Safety Reporting Requirements for INDs and BA/BE Studies	2025 Final Guidance: Sponsor Responsibilities — Safety Reporting Requirements and Safety Assessment for IND and BA/BE Studies
Primary Scope and Focus	Focused on procedural requirements for expedited reporting of individual Serious Adverse Events (SAEs).	Mandatory emphasis on safety assessment and aggregate data analysis to identify new, significant risks. Merges content with principles from the 2015 draft guidance on safety assessment.
Division of Responsibilities	Contained recommendations for both Sponsor and Investigator safety reporting responsibilities.	Exclusively focuses on Sponsor responsibilities. Investigator reporting recommendations are placed in a separate, concurrently issued guidance document.
Safety Surveillance/Planning	Implicit in the sponsor's duties, but lacked a formalized planning requirement.	Introduces the new term "Safety Surveillance Plan (SSP)" to describe a required systematic and organized approach.
Plan Components (SSP)	Did not specify formal plan components.	Requires the plan to include clearly defined roles and responsibilities, a process for regular review of SAEs, and a process for aggregate safety reviews.
Requirement for Review	Focused primarily on individual case review to determine if the reporting criteria (Serious, Unexpected, Suspected Adverse Reaction - SUSAR) were met.	Explicitly requires sponsors to review and evaluate all accumulating safety data at regular intervals (aggregate review) to update the overall safety profile.
Decision-Making Body	Lacked specific recommendations for the structure of the internal safety review process.	Offers greater flexibility by allowing the sponsor to choose the individual, group, or entity (e.g., Safety Assessment Committee) responsible for safety reporting and decision-making.
Source of Safety Data	Focused mainly on reports from the clinical trial itself.	Emphasizes that sponsors must review information from any source (e.g., animal studies, scientific literature, foreign reports, and commercial experience) to identify new significant risks to trial participants.
Expedited Reporting Rationale	The concern was the overreporting of uninformative individual Adverse Events (AEs), which hindered the IRB's ability to focus on true risks.	Seeks to reduce overreporting by clarifying that the decision for a 7- or 15-day expedited report must be based on the sponsor's professional judgment of causality (i.e., a reasonable possibility).

Summary of the Shift

The 2025 guidance strongly emphasizes a shift in the regulatory burden from volume-based individual reporting (the 2012 paradigm) to quality-based, comprehensive safety analysis by the sponsor. The overall goal is to enhance patient protection by focusing the FDA, IRBs, and investigators on truly meaningful safety signals derived from cumulative data, rather than individual case reports.

SAE reporting - from non-serious AE to serious AE - one event or two events?

An adverse event is any undesirable experience associated with the use of a medical product in a patient. The event is serious (therefore serious adverse event (SAE)) and should be reported when the patient outcome is:

Death

Report if you suspect that the death was an outcome of the adverse event, and include the date if known. 

Life-threatening

Report if suspected that the patient was at substantial risk of dying at the time of the adverse event, or use or continued use of the device or other medical product might have resulted in the death of the patient.

Hospitalization (initial or prolonged)

Report if admission to the hospital or prolongation of hospitalization was a result of the adverse event.

Emergency room visits that do not result in admission to the hospital should be evaluated for one of the other serious outcomes (e.g., life-threatening; required intervention to prevent permanent impairment or damage; other serious medically important event).

Disability or Permanent Damage

Report if the adverse event resulted in a substantial disruption of a person's ability to conduct normal life functions, i.e., the adverse event resulted in a significant, persistent or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities and/or quality of life.

Congenital Anomaly/Birth Defect

Report if you suspect that exposure to a medical product prior to conception or during pregnancy may have resulted in an adverse outcome in the child.

Required Intervention to Prevent Permanent Impairment or Damage (Devices)

Report if you believe that medical or surgical intervention was necessary to preclude permanent impairment of a body function, or prevent permanent damage to a body structure, either situation suspected to be due to the use of a medical product.

Other Serious (Important Medical Events)

Report when the event does not fit the other outcomes, but the event may jeopardize the patient and may require medical or surgical intervention (treatment) to prevent one of the other outcomes. Examples include allergic brochospasm (a serious problem with breathing) requiring treatment in an emergency room, serious blood dyscrasias (blood disorders) or seizures/convulsions that do not result in hospitalization. The development of drug dependence or drug abuse would also be examples of important medical events.

In clinical trial setting, there are two layers of SAE reporting:

The investigational site reports the SAE to the trial sponsor:

According to ICH E6 (Good Clinical Practice), the SAEs should be reported immediately to the sponsor when the site staff become aware of the occurrence of a SAE. 'Reported immediately' is generally interpreted as 'reported within 24 hours'. The clinical trial protocol typically includes a statement "Sites must report SAE information regardless of causality or expectedness to the Sponsor within 24 hours of awareness of an SAE." 

The sponsor or designee reports the SAEs and SUSAR to the regulatory authorities (FDA):

SAEs need to be reported to regulatory agencies and IRBs/ECs in narrative format (so called SAE narratives). According to 21CRF part 312.32 Safety Reporting, here are the requirements:

SUSUR stands for serious and unexpected suspected adverse reaction. FDA guidance "Safety Reporting Requirements for INDs and BA/BE Studies" provided the definition for SUSAR and specified the reporting requirement. 

SUSAR determination and subsequent reporting are typically handled by the drug safety or pharmacovigilance group, which has access to treatment assignment information. When a SUSAR event is reported, the drug safety or pharmacovigilance group may unblind the individual subject to determine if they are in the active drug group or the placebo group. If the subject is in the placebo group, it will not be considered a SUSAR.

SUSAR events that involve unexpected fatal or life-threatening suspected adverse reactions must be reported to the FDA within 7 days through the submission of a "7-day IND safety report." Here is what is said in 21CFR part 312.32 IND Safety Reporting:

In practice, it is common for adverse events to initially present as non-serious (not meeting the criteria for defining a serious adverse event), but with the event worsening, they may evolve into a serious adverse event. For example, a subject may experience an adverse event that eventually requires hospitalization, meeting the criteria for a serious adverse event.

There is a common (but inappropriate) approach to handling this situation by splitting the event into two separate entries: one for the initial non-serious adverse event and another for the subsequent serious adverse event. Some sponsors provide instructions to record the non-serious adverse event with a stop date, mark the outcome as 'Not recovered/not resolved,' and create a new entry for the serious adverse event with the start date when the seriousness criteria are met. The stop date of the non-serious adverse event should be the same date or the day prior to the start date of the serious adverse event. While this approach aligns with SAE reporting and is considered conservative, it artificially divides the same episode into two separate events, which will cause the problem when writing the SAE narratives. We can not just write a SAE narrative without including the non-serious part - they are essentially the same event. 

In general, when an adverse event initially presents with non-serious symptoms and later progresses to meet the criteria for a serious adverse event (SAE), it is typically reported once as an SAE. This is because the serious adverse event designation takes precedence over the non-serious symptoms.

It's important to note that the onset date of the SAE should be the date when the symptoms started, not the date when the SAE criteria are met. Reporting of SAEs should be based on the date when the SAE criteria are met and when the site staff becomes aware of the SAE.

In situations where an adverse event starts as non-serious and progresses to serious, it is appropriate to report the event as an SAE.

When an adverse event evolves into a serious condition, such as requiring hospitalization or meeting other predefined criteria for seriousness, it is considered a new phase or stage of the same event. Reporting it as an SAE captures the escalated severity and ensures appropriate attention, monitoring, and reporting to regulatory authorities.

When an adverse event (AE) starts as non-serious and progresses to a serious state, it should be reported solely as a serious adverse event (SAE). In this situation, there are three potentially relevant dates: the "serious adverse event start date," "adverse event becomes serious," and "the site staff became aware of the serious adverse event." These terms are associated with the reporting and monitoring of adverse events in clinical trials or medical research. Here's a comparison of these terms:

Serious Adverse Event Start Date: The serious adverse event start date refers to the specific date when an adverse event initially occurred or began in a participant during a clinical trial or medical research study. It marks the beginning of the event's timeline and is often recorded to establish the temporal relationship between the event and the study procedures.

Adverse Event Becomes Serious: An adverse event refers to any unfavorable or undesirable medical occurrence experienced by a participant during a clinical trial or medical research study, regardless of its seriousness. When an adverse event becomes serious, it means that the event has worsened in intensity, severity, or clinical impact. The criteria for determining whether an adverse event is considered serious may vary, but they generally include outcomes such as death, life-threatening situations, hospitalization or prolonged hospital stay, significant disability, congenital anomalies, or other important medical events.

The Site Staff Became Aware of the Serious Adverse Event: This phrase signifies the point at which the staff at the clinical trial site or research facility becomes aware of the occurrence of a serious adverse event in a participant. It is crucial to promptly report and document the event to ensure participant safety and adhere to regulatory requirements. The site staff's awareness triggers subsequent actions such as assessment, documentation, reporting to the appropriate authorities, and potential modifications to the study protocol or participant management.

In summary, when an adverse event starts as non-serious and progresses to a serious state, it should be reported solely as a serious adverse event (SAE). The serious adverse event start date marks the initial occurrence of the event, while the "adverse event becomes serious" indicates the worsening of its intensity or impact. The "site staff became aware of the serious adverse event" signifies the point when the research facility staff acknowledges the occurrence and initiates the necessary actions for reporting and participant safety.

Regulatory Education for Industry (REdI) Annual Conference 2023 - Slides and Recordings

Early this month, FDA conducted 'Regulatory Education for Industry (REdl) Annual Conference 2023'. This annual conference provided opportunity for health care industry professionals to Learn directly from the FDA’s regulatory experts in medical product centers: drugs, devices, and biologics. The course from annual conference is designed to provide participants with a strong, basic foundation in the FDA’s regulatory requirements, and also create awareness of current activities.

• The flyer about this conference: https://www.fda.gov/drugs/news-events-human-drugs/regulatory-education-industry-redi-annual-conference-2023-06052023
• The agenda for the conference: https://sbiaevents.com/files2023/REdI-2023-Agenda.pdf

All the FDA presentation can be watched on Youtube and the presentation slides are listed in the tables. 

There are two presentations by FDA statisticians: Dr Andrew Potter on "Reviewer’s Perspective on Data Collected by Wearable Digital Health Technology in Clinical Trials" and Dr John Scott on "FDA’s Implementation of the Estimand Framework and Complex Innovative Trial Design Meeting Program".

Plenary + Drugs Day 1:

User Fee Impact on FDA Programs Jeff Shuren, Patrizia Cavazzoni, Peter Marks

Biosimilar Program Updates and What’s New Under BsUFA III Stacey Ricci and Kimberly Maxfield

FDA Formal Meetings: What’s New under PDUFA, BsUFA, and OMUFA Elizabeth Thompson

Electronic Submission Gateway (ESG): The Road to Modernization Jessica Bernhardt

ECTD v4.0 Implementation Update Jonathan Resnick

eCTD: More than a Document Heather Crandall

CDER-CBER Data Standards Program Ray Wang

Reviewer’s Perspective on Data Collected by Wearable Digital Health Technology in Clinical Trials Andrew Potter

PDUFA VII Goals For Digital Health Technologies – A Technical Perspective Marry Ann Slack

Drugs Day 2: 

Leveraging Small Business and Industry Assistance (SBIA) Resources Renu Lal

Overview of FDA Split Real Time Application Review (STAR) Pilot Program LaShawn Schnupp

Use-Related Risk Analysis (URRA) and Human Factors (HF) Protocol Reviews: What to Submit for an Efficient Review Lolita Sterrett

The Modernization of Clinical Trials through Digital Health Technologies (DHTs), Decentralized Clinical Trials (DCTs), and Point of Care Trials Elizabeth Kunkoski

PDUFA VII Real-World Evidence Kimberly A. Smith

New PDUFA VII Commitments: Pre-approval & Post-approval Postmarketing Requirements (PMRs) Kathleen Weil

How CDER is Accelerating Rare Disease Cures and the PDUFA VII Rare Disease Endpoints Advancement Pilot Program Kerry Jo Lee

Chemistry, Manufacturing, and Controls Assessment for Expedited Programs Paresma Patel

Best Practices for Drug Product Recalls Doris Chin

Devices Day 1:

Medical Device Regulatory Framework: Where to Start? Kendra Holter

Biocompatibility Basics Jennifer Goode

Streamlining Conformity Assessment: Putting Standards to Work Scott A. Colburn

Detangling the 510(k) Process Andrew Sprau

CDRH Portal Overview and Feature Walkthrough Nelson Anderson

Reduced Medical Device User Fees: Small Business Determination (SBD) Program Jason Brookbank

Managing Medical Device Nonconforming Product with Quality Ruth Bediakoh

Handling Medical Device Compliant Files with Quality Tonya Wilbon

Devices Day 2/Biologics Day 1:

Addressing Regulatory Science Gaps in Artificial Intelligence (AI) / Machine Learning (ML) Alexej Gossmann

Radiation-Emitting Medical Device Update Laurel Burk

CDRH Medical Device Import Overview Yvette Montes

All about the Form FDA 483 and the ORA Electronic Reading Room William Chang

PDUFA VII Enhancements - Interaction with OTP Mara Miller

Overview of PREA, PSPs plus an Introduction to the Rare Pediatric Disease (RPD) Priority Review Voucher Program Adrienne Hornatko-Munoz

Nonclinical Development for Cellular and Gene Therapy Products from the Perspective of CBER/FDA Ernesto F. Moreira

Nonclinical Considerations for the Development of Cell and Gene Therapy Products for IND Submissions Gregory Conway

Clinical Readiness for IND Submissions Shelby Elenburg

Design Considerations for Clinical Trials in Rare Diseases

Rosa Sherafat

 

Biologics Day 2:

CMC Development and Readiness Pilot (CDRP) Program Ramjay S. Vatsan

CMC Considerations for Tissue Engineered Product Development Wen (Arron) J. Seeto

Identifying and Controlling Attributes Related to Potency for Cell and Gene Therapy Products Matthew Klinker

FDA’s Implementation of the Estimand Framework and Complex Innovative Trial Design Meeting Program John Scott

Postmarketing Safety and Pharmacovigilance for Vaccines Meghna Alimchandani

Expanded Access to Investigational Drugs for Treatment Use Lei Xu

CBER Inspections of Facilities for Biological Products Wei Wang