Clinical Trials Regulation (EU) No. 536/2014 – The Impact on Annual Safety Reporting

On 31 January 2022, the European Union (EU) Clinical Trials Regulation (CTR) No. 536/2014 replaced the Clinical Trials Directive (European Commission) No. 2001/20/EC to harmonize the processes for assessment and supervision of clinical trials throughout the EU.¹ This blog highlights the additional requirements for annual safety reports (ASRs) and their impact on authoring.

Topics impacting annual drug safety reporting

To support the implementation of CTR (EU) No. 536/2014, a questions and answers (Q&A) guidance document was released (current version 7.1; March 2025),² which details additional requirements for the submission of the ASR otherwise known as a development safety update report [DSUR]) in the EU.

1. Reference safety information

The Reference Safety Information (RSI) is used to assess the expectedness of all ‘suspected’ serious adverse reactions (SARs) that occur in clinical trials. The RSI typically forms part of the Investigator’s brochure (IB). The CTR (EU) No. 536/2014 Q&A guidance document recommends updating the RSI section of the IB once a year in alignment with the DSUR, which should be submitted within 1 month of the DSUR. This approach is depicted in Figure 1.

The example in Figure 1 shows that the updated RSI (IB v.6) aligns with the data lock point (DLP) of DSUR#9 and is submitted in parallel with DSUR#9. Following the approval of IB v.6 by the first Member State (where a trial with the investigational medicinal product is ongoing), IB v.6 should then be used for expedited suspected unexpected serious adverse reaction (SUSAR) reporting and the identification of SUSARs in the ‘Cumulative summary tabulation of serious adverse reactions’ in DSUR#10.

Using an RSI in effect at the “end” of a reporting period may seem contradictory with the International Council for Harmonisation (ICH) E2F guidelines.³ However, IB v.6 can be considered in effect at the “beginning” of the reporting period as the data therein are aligned with the DLP of DSUR#9 and thus the “beginning” of the reporting period for DSUR#10. This approach also aligns with the Clinical Trial Facilitation Group (CTFG) Q&A document released in 2017.⁴

2. Regional requirements

The CTR (EU) No. 536/2014 Q&A guidance document also provides updated “Region-Specific Information” that is required in the DSUR submitted to the EU/European Economic Area (EEA) including:

1. Cumulative summary tabulation of SARs
2. List of subjects who died during the reporting period
3. List of subjects who dropped out of clinical trials in association with an adverse event during the reporting period
4. Safety signals review: additional information and appendix to present a high-level overview of the safety review process in the DSUR reporting period. Present the details and outcome of the safety signal review process during the DSUR reporting period in a table (like a periodic safety update report).
5. EU clinical trial numbers of relevant trials should be listed alongside the protocol code.

Whilst the first 3 items listed above are consistent with the ICH E2F guidelines,³ items 2 and 3 have typically only been associated with regional appendices for the United States and are now a requirement for DSURs submitted to the EU/EEA. Item 4 aligns with the previously released guidance from the Medicines and Healthcare products Regulatory Agency/Health Canada⁵ in 2021. If signal evaluations for clinical trials are not possible/appropriate, then justification should be provided for not including the signal information. Item 5 is best addressed in Appendix 3 of the DSUR (Status of Ongoing and Completed Clinical Trials).

3. Removal of subject identifiers in data line listings

The CTR (EU) No. 536/2014 Q&A guidance document states that in order to comply with Article 43.3 of the CTR and protect patients’ rights, the line listing of SARs (in Appendix 5 of the DSUR) should identify SARs using the case identification (ID) and Study ID “without including subject ID,” and that the listing of subjects who withdrew from the study due to adverse events and the listing of subjects who died during the reporting period (refer to Section 2 above) should “not allow the identification of natural persons.”

Therefore, sponsors should not include clinical trial subject ID numbers in the line listings of SARs, the list of subjects who died during the reporting period, and the list of subjects who dropped out of studies during the reporting period due to adverse events.

4. Cumulative summary tabulations of serious adverse events

The CTR (EU) No. 536/2014 Q&A guidance document suggests improving Section 7.3 of the DSUR ‘Cumulative Summary Tabulations of Serious Adverse Events’ by including the “absolute numbers of patients that have been treated.” This can be presented either within the body text of the DSUR or in the column headings of the Cumulative Summary Tabulation of Serious Adverse Events itself (in Appendix 6 of the DSUR), as illustrated below; adapted from the CTR (EU) No. 536/2014 Q&A guidance document.²

How can we help?

These requirements apply to submissions to EU/EEA. However, sponsors often submit DSURs globally. Thus, they should also follow other regional guidelines. In the context of DSURs, sponsors must be mindful of both EU/EEA and other international requirements, ensuring compliance with a complex landscape of regional guidelines and deadlines.