FDA updates set the stage for broader use of harmonized standards for safety reporting

Submission of individual case safety reports and the family of ICH E2 guidelines

• The International Council for Harmonization’s (ICH) E2 guidelines were created to facilitate the timely and standardized exchange of information from sponsors to regulators on serious and urgent safety issues arising from the use of biopharmaceutical products. While all products bear some level of risk to patients (no matter how miniscule), when serious and unexpected events occur, regulators want to be kept in the loop so that they can determine whether a product’s potential risk to patients outweigh its potential benefit. Broadly, the E2 guidelines provide a framework for sponsors to determine how and when new information on product use should be disseminated to regulators—either immediately in the form of Individual Case Safety Reports (ICSRs) or later on in a different submission type (e.g., Periodic Benefit-Risk Evaluation Reports). Since these issues could occur during the investigational phase of clinical development as well as in the post-marketing setting—and product status could very well differ by country/region—ICH members determined that these guidelines should be developed to facilitate the exchange of information in both settings. This way, regulators in each jurisdiction would be rapidly informed and could take swift action on product use, regardless of its marketing status.
• In sum, there are essentially four scenarios that the E2 guidelines cover: 1) Expedited reporting of ICSRs linked to investigational products (ICH E2A); 2) Expedited reporting of ICSRs linked to currently marketed products (ICH E2D); 3) Periodic reporting of safety information for products under investigation (ICH E2F); and 4) Periodic reporting of safety/benefit information (PBRERs) for currently marketed products (ICH E2C). Of note, ICH E2F covers all investigational products in addition to any currently marketed products that are being further studied. An outlier, the E2E Guideline, doesn’t provide recommendations on reporting information; instead, it advises sponsors on issues to consider when designing their “ prospective planning of pharmacovigilance activities.”
• The other outlier, the E2B Guideline (omitted from the categories above) has a more complicated purpose and history. Unlike the other guidelines on reporting information, it was intended to provide definitions of “common data elements” that should be included in the transmission of information described in Individual Case Safety Reports, meaning its contents had important implications for the recommendations contained in the E2A and E2D guidelines. According to the original E2B Guideline, the information transmitted on ICSRs should be formatted with one section on the source of the data and another that provided details on the actual case itself (e.g., patient and product characteristics). The E2B Guideline was first finalized by FDA in January 1998, though the guideline was subsequently revised several times in just the next few years.
• In the years that followed, it became clear that due to underlying differences in legislative frameworks for different countries/regions, coupled with the rapidly evolving landscape of data elements, product types, and data standards; it would be a challenge for any version of the E2B Guideline to remain current. When the document was taken back to the drawing board again in 2003, it remained on hold for more than a decade until a final version was agreed upon in 2012, with the FDA officially adopting it in 2014. That revised version remains in use today (more on this below).
• Part of the reason it took so long for the E2B document to be revised, and why its relevance has endured, is because it was the first guideline that was “re-envisioned” following the ICH’s decision to stop developing its own electronic messaging standards to accompany guidelines on data elements. Instead of dedicating its own (limited) resources to the continual redevelopment of data exchange standards, ICH instead decided to collaborate with standards development organizations (SDOs) on this aspect of the safety reporting process, leveraging their networks of experts and additional resources to do so. Using this new model, the ICH contributed to the development of data exchange standards led primarily by the International Organisation for Standardisation (ISO), the Health Level Seven (HL7), the European Committee for Standardisation (CEN), and the Clinical Data Interchange Standards Consortium (CDISC). Furthermore, the use of technical specifications developed by SDOs were anticipated to enable “wider inter-operability” across different regions and different healthcare sectors.
• What makes the re-envisioned version of the E2B(R3) Guideline especially unique is that it is not a single document. As was noted in the explanation released by ICH at the time, revision three is a collection of four items, only two of which are actually guidance documents. The two guidance documents were: an implementation guide and a “backwards and forwards compatibility document.” The other two items consisted of an example XML file demonstrating proper coding of an ICSR and a folder of “XML schema files” which provided the rules, elements, and attributes necessary to construct, export, read, and validate ICSR messages.

Implementation challenges & the gradual transition to E2B(R3)

• Since many sponsors had already transitioned to the use of the E2B(R2) Guideline almost ten years prior to the complete redesign of the E2B guideline, stakeholders agreed that a gradual transition from the second to third revision of the guideline was called for. To ease sponsors’ transition from the old E2B guideline (R2) to the updated version (R3), the ICH has developed a string of additional Q&A and implementation guides to accompany the initially released E2B files. Likewise, regional health authorities have also developed their own guidances, technical specification guides, Q&A documents, and example files to provide additional context for industry on how the E2B(R3) changes will take shape within their individual submission systems.
• In addition to providing support to industry, many regulators also had to make major changes to their own submission systems, many of which were designed according to the pre-R3 guidelines. In fact, the timing of this changeup was particularly inconvenient for the FDA, given other processes already in motion. In 2012, the passage of the FDA Safety and Innovation Act (FDASIA) created a new requirement for sponsors to submit all drug submissions, including clinical trial applications, in an electronic format as specified by FDA guidance. While there are today several options which sponsors can use to submit applications electronically (dependent on product review center), the first—and the only—agency-wide tool for online application submission remains the Electronic Submissions Gateway (ESG). Two years later, the FDA issued a final rule that extended electronic submission requirements to postmarketing safety reports as well. While the ESG offered one method for electronic submission of case reports, the FDA also recognized that users unfamiliar with the system faced certain challenges in submitting ICSRs this way.
• With this issue in mind, the Agency also developed an easy-to-use “web-based submission portal” that provided an alternative method for ICSR submission. The platform, called the Safety Reporting Portal (SRP), offered a fillable form that industry and medical professionals alike could use to submit the necessary case information without specialized training. Upon submission, the information would be uploaded directly to the new FDA Adverse Event Reporting System (FAERS) database—a process that Agency staff previously had to perform manually following the receipt of paper reports. While the SRP could be used to submit information on drugs and biological products, the only exception was for vaccines. The FDA created a parallel tool, called the eSubmitter which worked like the SRP with the caveat that case information was not uploaded to FAERS but to the Vaccine Adverse Event Reporting System (VAERS), a program co-monitored by both the FDA and the Centers for Disease Control and Prevention (CDC). Of note, one drawback to case report submission via either of these alternative portals was that each case had to be filled out one-by-one. For users with multiple case reports to upload at once, the ESG offered a far more efficient option as it enabled users to connect directly to their internal databases and mass upload a series of case reports (i.e., database-to-database submissions).
• While the gradual transition to the E2B(R3) Guideline specifications and standards does not impact the submission of ICSRs through FDA’s Safety Reporting Portal, the Agency has been gradually rolling out the E2B(R3) requirements for sponsors utilizing the database-to-database submission of case reports via the Electronic Submissions Gateway. Starting just recently in mid-January 2024, FDA began accepting post-marketing ICSRs in the E2B(R3)-format. This change aligned well with the Agency’s adoption of the new ICH E2D Guideline on expedited reporting of post-approval ICSRs. The revision—the first since the document was finalized in 2003—included significant changes meant to reflect how patient data are collected in a digital world that did not fully exist two decades ago. Namely, the use of “social media, market research programs, patient support and assistance programs,” as noted in the concept paper, have now been addressed. [Read Agency IQ’s analysis of the draft guideline here]
• Along with its announcement of the draft guideline, the ICH also published an “explanatory note” describing how the new E2D guideline should be used in conjunction with the existing E2B guideline, today and in the future. The note explained that since the E2D Guideline refers to the E2B Guideline for recommendations on translating the information collected on individual cases into data elements for submission, sponsors will likely have questions about the use of new data sources (e.g., social media). In fact, some of the values referred to in the revised draft guideline – PSPs, MRPs, digital platforms – do not currently exist and would need to be added to ICH E2B(R3). Once E2D(R1) has been finalized following comments received during public consultation, the note stated that “the final changes will be published via the E2B(R3) Implementation Guide package and ICH E2B(R3) Questions and Answers document.”

This week, the FDA made significant progress towards the full implementation of E2B(R3) requirements.

• To start, the FDA just announced yesterday that sponsors can now—as of April 1, 2024—submit ICSRs involving the use of investigational products (i.e., Investigational New Drug, or IND, safety reports) to the FDA in E2B(R3) format. Likewise, sponsors can now also submit ICSRs which pertain to the conduct of IND-exempt in vivo BA/BE studies (i.e., IND-exempt BA/BE safety reports). While the electronic submission of ICSRs in the latter case is voluntary, the first is not.
• Sponsors will have 24 months to get comfortable submitting IND safety reports in E2B(R3) format before compliance becomes mandatory in April 2026. For sponsors who choose to make the leap sooner, there is no going back; the FDA notes that once the E2B(R3) format is used once by sponsors to submit ICSRs, companies are not permitted to “revert to legacy methods or standards.” In any case, for sponsors who choose to submit ICSRs using the FDA’s Safety Reporting Portal instead of submitting case reports via database-to-database transmission (i.e., using the FDA’s electronic submissions gateway), no changes are necessary.
• Secondly, the FDA also released three final guidances on the submission of ICSRs in E2B(R3) format: 1) Providing Regulatory Submissions in Electronic Format: IND Safety Reports; 2) FDA Regional Implementation Guide for E2B(R3) Electronic Transmission of Individual Case Safety Reports for Drug and Biological Products; and 3) Electronic Submission of Expedited Safety Reports From IND-Exempt BA/BE Studies.
• The history for each document, along with the additional guidances and technical documents which cross-reference these guidances are included in the table below. Each of the new documents is technical in nature and requires a baseline understanding of the ICSR submission process; however, a few highlights are noted.
• FDA Regional Implementation Guide for E2B(R3) Electronic Transmission of Individual Case Safety Reports for Drug and Biological Products: In short, this guidance provides an overview of where ICSRs submitted to the FDA may deviate from (or add to) the terminology and data elements that are described in ICH guidelines. For example, ICSRs submitted in the United States may use certain terminology drawn from the National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS) code set, which wouldn’t be applicable in other regions and thus are not included in internationally harmonized guidelines or technical supplements. Likewise, the FDA has a plethora of data elements it requires to be included in ICSRs pertaining to combination products. In any case, the guidance explains that while there may be unique regional terminology and/or data elements that FDA requires which are different from other health authorities, these add-ons still conform to the “data element definitions, formats, and use (e.g., required or optional) as specified by the ISO/HL7 27953-2:2011 standard and in accordance with the content specifications described in the E2B(R3) Electronic Transmission of ICSRs Implementation Guide.”
• Providing Regulatory Submissions in Electronic Format: IND Safety Reports: The updated guidance applies only to “IND safety reports for serious and unexpected suspected adverse reactions required under 21 CFR 312.32(c), which includes both 7- and 15-day reporting requirements depending on the severity of the event.” One exception to these requirements is when it comes to the submission of case reports under noncommercial INDs. Per the guidance, this means products that are not intended for commercial distribution, are provided via expanded access, or which are being evaluated via an investigator-sponsored IND, are not required to submit ICSRs to FDA electronically (and therefore, do not need to adhere to the E2B(R3) requirements). Again, the guidance also reiterates that sponsors do not have to use the updated E2B(R3) standards if they choose to submit ICSRs using the SRP instead of submitting them via the ESG.
• Electronic Submission of Expedited Safety Reports From IND-Exempt BA/BE Studies: The least technical (and the shortest) of the new guidances on electronic submission of ICSRs, this guidance describes how sponsors or investigators conducting IND-exempt BA/BE studies should submit ICSRs electronically, if they choose to do so. For BA/BE studies that do not require INDs (a majority of those used in support of generic drug applications), only a subset of FDA’s regulations regarding clinical research apply. This was an area that FDA investigators recently interviewed by the U.S. Government Accountability Office (GAO) flagged as a major concern. In fact, for IND-exempt in vivo BA/BE studies, there are three general requirements which do apply, as are outlined in 21 CFR 320.31(d). While the third category of requirements for these studies are that investigators must notify FDA of certain adverse events within 7 or 15 days (depending on severity), there are no requirements for these reports to be submitted to FDA electronically.
• For sponsors who volunteer to make these submissions voluntarily, the new final guidance outlines best practices. If not, investigators can still opt to submit this information by filling out Form FDA 3500A and submitting it to FDA’s Office of Generic Drugs by email, through fax, or even by phone. However, the guidance encourages persons conducting these studies to consider switching to the electronic submission of ICSRs using FDA’s other options (e.g., through ESG, which transmits reports to FAERS or through the SRP) instead. For those considering the switch, the guidance says that FDA’s “FAERS electronic submissions coordinator will assist submitters to help ensure that all steps are completed for successful submission of ICSRs and ICSR attachments.”
• A final note: Importantly, the guidance explains that FDA’s expedited reporting requirements do not apply to IND-exempt in vivo BA/BE studies conducted outside the United States. In any case, adverse event reporting information from these studies are still expected to be included in the ANDAs submitted to FDA.

FDA guidances regarding the implementation of E2B(R3) and the submission of ICSRs

To contact the author of this item, please email Rachel Coe ( [email protected]).
To contact the editor of this item, please email Alexander Gaffney ( [email protected]).

Key documents

• Providing Regulatory Submissions in Electronic Format: Investigational New Drug Application Safety Reports; Guidance for Industry
• FDA Regional Implementation Guide for E2B(R3) Electronic Transmission of Individual Case Safety Reports for Drug and Biological Products
• Electronic Submission of Expedited Safety Reports From Investigational New Drug-Exempt Bioavailability/Bioequivalence Studies; Guidance for Industry