What you need to know for compliance

Last year the US Food and Drug Administration (FDA) increased momentum in terms of upgrade of the FDA Adverse Event Reporting System (FAERS). At the end of last year, the FDA released a roadmap for industry to allow implementation of Investigational New Drug (IND) safety reporting from paper eCTD format to E2B format. Initially the FDA will accept reports in E2B (R2) format along with the current paper eCTD format and from this year at the end of April 2020 the FDA will accept E2B (R3) format submissions. As for all legislative updates, particularly those involving technical change, sponsors are required to ensure intense change management planning to bring efficiency to their safety reporting processes and to ensure compliance.

Background - global electronic safety reporting

Over the last decade, as the volume of safety reports has increased, exchange of Individual Case Safety Reports (ICSRs) across the world has progressively shifted from paper-based to an electronic format. The electronic transmission of case safety information in standardised format has become an important component of global pharmacovigilance to allow for efficient transmission of safety data, monitoring and tracking safety signals to enhance patient safety.

The world of pharmacovigilance strives for a standard report format due to the increase in complexity and globalisation of trials. To support this, the International Conference of Harmonisation (ICH) has defined E2B as an international standard for transmitting adverse event reports. In time, the need to exchange a high volume of safety information worldwide efficiently and automatically requires periodic revision of the E2B documents. In 2001, ICH released E2B (R2) and since then, there have been many changes in regulatory reporting requirements and pharmacovigilance practices globally.

The recent revision E2B (R3) is based on the international standard HL7 ICSR model, which is capable of supporting exchange of human medicinal products, medicinal devices and veterinary products. This benefits interoperability and allows exchange of safety data in standard transmittable ICSR messages, irrespective of source and destination through various E2B compliant systems. 

The European Medicines Agency (EMA) and regulatory authorities in Japan and China have progressed to adopt and accept E2B (R3) format safety submissions. Multiple other countries are also rapidly progressing in this direction.

Current methods - clinical safety reporting to the FDA

Currently, the FDA requires sponsors to submit PDF files of MedWatch or CIOMS using the eCTD structure format. Due to the PDF format of these safety reports, the review and tracking by sponsors and the FDA is inefficient and labour intensive.

Changes to clinical safety reporting to the FDA – are there any advantages?

The FDA will leverage the IND safety reporting process for clinical safety so that it is in line with the already accepted E2B format for post-marketing submissions. The FDA have already successfully completed a pilot phase to configure FAERS to accept IND safety reports in E2B format.

After release of the FAERS II project, the FDA has indicated that the sponsor would adopt the process depicted in Figure 1 for reporting of IND safety reports. By changing to safety reporting in E2B format, the review and analysis of safety data by the FDA will be efficient and help the FDA to track potential safety signals from clinical studies. This will also benefit sponsors that report to many key regulatory agencies across the world, due to the development of a consistent format for submission that complies with ICH guidelines, as well as alignment with the FDA post marketing requirements. A sponsor may also set up gateway-to-gateway submission from their safety database to the FDA for automated reporting, streamlining the process further.

Figure 1: IND safety report Data Flow

Will there be any action required by sponsors to be compliant with the FDA E2B R3 reporting – in the form of IND specific E2B data elements?

IND-specific E2B data elements are critical to ensure legal regulatory requirements are met, so it will be important for Sponsors to adopt the E2B R3 regional elements imposed by the FDA. The FDA have indicated that there will be E2B R3 regional elements to comply with. This requires intense change management planning and testing to ensure compliance.

What are the timelines published for sponsors to start IND safety reporting in E2B format to the FDA?

A confirmed mandatory date for R3 submissions is yet to be announced by the FDA, however, Sponsors are expected to start testing from April 2020.  Sponsors can continue to submit ICSRs in R2 format until ready for R3 submission. FDA will update the FAERS website with information indicating when to start voluntary reporting in E2B (R2) format; this has been announced to tentatively be January 2020. Until further notice, the FDA will accept IND safety in eCTD structure as per the most recent effective version of the eCTD guidance. Before the R3 mandated date, FDA will accept IND safety reports as part of a voluntary submission program, which is the preferred route of submission.  

Figure 2: Plan for IND safety reporting in E2B (R2 or R3) format.

What if a sponsor does not host an E2B compliant safety database or are not ready to start country level E2B reporting?

Navigating regulatory legislations and guidelines is a constant challenge that pharmaceutical organisations have to confront in order to ensure patient safety, as well as to avoid any dismal consequences that can be imposed by regulatory authorities.

At ICON, we have an E2B (R3) compliant safety database to allow for compliance as further countries, including the US, come on-board. We are also intricately analysing the legislation to monitor for country level differences in E2B submissions to ensure successful testing and implementation and do this via our dedicated pharmacovigilance regulatory intelligence group based in the EU.

For more information on how to navigate this latest regulatory development contact us



  • Providing Regulatory Submission in Electronic Format: IND Safety Reports, Draft Guidance for Industry (October 2019)
  • Digital submission of adverse event reports for investigational new drug applications reflects FDAs ongoing modernisation efforts (October 2019)
  • Electronic Submission of IND Safety reports – Technical Conformance Guide (October 2019)
  • Revised Specifications for Preparing and Submitting Electronic ICSRs and ICSR Attachments (September 2019)