Updated Version of the Clinical Trials Regulation Questions & Answers Paper

The European Commission (EC) recently published an updated Version of the Questions & Answers relating to the Clinical Trials Regulation (EU) No 536/2014 (CTR). The revision has been submitted for discussion to the Expert Group on Clinical Trials. The Q&As were discussed progressively since December 2014 and the final draft (Version 1) was finalized in April 2018. The Q&As enter into force on application of the CTR which depends on the notice of the full functionality of the CTIS.

Changes compared to superseded version 1 are inclusion of Q&As on safety (7.1-7.47) and updates to Q&As 1.15, 3.1, 5.2, 5.7, 10.10. 
Chapter 7 on “Safety Reporting” was drafted by the Clinical Trials Facilitation and Coordination Group of the Heads of Medicines Agency and endorsed by the Expert Group on Clinical Trials of the EC. The following shows an extract of chapter 7:

7a DEFINITIONS (Q&As 7.1-7.6)

  • 7.3 What is the difference between an Adverse Event and an Adverse Reaction?
    An AR, in contrast to an AE, is characterized by the fact that a causal relationship between a medicinal product (MP) and an occurrence is suspected. It could also be related to the administration procedure when the procedure is an essential part of the investigational MP (IMP) administration.
  • 7.4 What is a Serious Adverse Reaction?
    SARs are defined as all noxious and unintended responses to an IMP related to any dose administered that result in death, are life-threatening, require patient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability or incapacity, or are a congenital anomaly or birth defect.
  • 7.6 What is the difference between seriousness and severity?
    Severity refers to the intensity of the event / reaction and is often classified by its effect on the everyday living of the subject as mild, moderate or severe. Seriousness refers to the outcome or action criteria of an AE or AR and serves as a guide for defining regulatory reporting obligations.


  • 7.7 What is the purpose of the Reference Safety Information and what should it contain?
    The RSI is used for the assessment of the expectedness of all ‘suspected’ SARs that occur in clinical trials (CTs). The content of the RSI should be a list of expected SARs and their frequencies. These ‘expected SARs’ should be restricted to ‘suspected’ SARs that were previously observed more than once, where, after a thorough assessment by the sponsor, reasonable evidence of a causal relationship between the event and the IMP exists. 
  • 7.8 Which document should contain the Reference Safety Information?
    The RSI of an IMP without an EU marketing authorization (MA) should always be a clearly separated specific section within the Investigator's Brochure (IB). For an IMP with an EU MA, which is used according to the MA, the RSI should be section 4.8. ‘Undesirable Effects’ of the appropriate SmPC (summary of product characteristics). If the IMP has a MA in several Member States (MSs) concerned with different SmPCs, the sponsor should justify its selection of the most appropriate SmPC as the RSI, with reference to subject safety.
  • 7.9 Which format should be chosen for the Reference Safety Information?
    The RSI should be presented in the form of a table, where the nature of the ‘expected SARs’ must be listed by MedDRA body System Organ Class (SOC) and Preferred Terms (PTs) followed by the frequency. The latest MedDRA version should always be used.


  • 7.20 How should relevant information on Suspected Unexpected Serious Adverse Reactions (SUSARs) be reported to member states?
    In addition to the data that is required to be reported on SUSARs, the sponsor must report all information that is ‘relevant’, i.e. the information which is necessary.
  • 7.21 Is unblinding necessary in case of SAR being unexpected for either the experimental IMP or comparator IMP? And who should unblind and be unblinded?
    The sponsor shall unblind the treatment allocation of only the affected subject to whom the SUSAR relates. The unblinding is not necessary for SARs assessed as expected for both, unless needed for the patient safety reasons.
  • 7.23 How to deal with safety issues not falling within the definition of SUSARs?
    They might require other immediate action, such as: Expedite reporting to the sponsor as defined in the protocol, regular reporting to the NCAs and Ethics Committees, urgent safety measures and their notification, notification of unexpected event changing the benefit-risk of the CT, substantial modifications of the CT, and early termination or temporary halt of the trial and their notifications.
  • 7.28 Should sponsors also send SUSARs to investigators of a CT?
    The sponsor should promptly notify all concerned investigators / institutions of findings that could adversely affect the safety of the subjects and should expedite the reporting of all SUSARs to all concerned investigators / institutions.
  • 7.29 When do requirements to record and report safety issues start and end for the investigator and the sponsor?
    AEs, including SAEs, should be recorded by the sponsor and the investigator from the signature of informed consent (IC) to the end of the trial. SARs or follow-up information for a SAR that the investigator becomes aware of after the end of the trial should be reported to the sponsor. The sponsor shall report all SUSARs from the beginning to the end of the trial and after the trial, within the timelines defined in the CTR. SOPs should be followed to ensure compliance at every stage of case documentation, data collection, validation, evaluation, archiving, reporting and follow-up.


  • 7.38 Is an ASR required for all drugs in the CT, like comparators, placebos or auxiliary medicinal products (AxMP)?
    As defined in the CTR an IMP means a medicinal product which is being tested or used as a reference, including as a placebo, in a CT. According to the CTR, an ASR is required for all IMPs other than placebos. For a reference compound (active or placebo), safety information could also be taken up in the ASR of the test IMP. A separate ASR for an AxMP is not required. However, if necessary, relevant safety information on AxMPs similar to reference compound should be addressed in the ASR of the IMP.
  • 7.43 Which are the responsibilities of the investigator and sponsor with regards to monitoring and safety reporting of ATIMPs?
    Regarding clinical trials with advanced therapies, general rules as well as IMP specific guidance apply which is contained in the detailed guidelines on GCP specific to ATMPs (expected to be published in 2019).



  • 7.46 How to submit ASRs during the transition period from the EU Directive 2001/20 to the CTR?
    In case one CT is ongoing in alignment with the CTR while others are under the Directive, an ASR should be submitted to the database specified in the regulation. Sponsors are allowed to name all MSs concerned for all ongoing CTs in EU/EEA within the Directive as well as CTR. Sponsors are still obliged to submit ASRs to Ethics Committees according to national legislations in MSs with ongoing CTs within the Directive and inform investigators of any new safety data or change in benefit-risk evaluation.
  • 7.47 How to report SUSARs during transition time from Directive 2001/20/EC to CTR?
    SUSARs need to be reported to the EV (Eudravigilance) database. Double reporting is to be avoided, unless the NCA (National competent authority) has had a national requirement for direct reporting of SUSARs. In addition, despite reporting to NCAs via EV, the reporting obligations still need to be respected, especially reporting to Ethics Committees according to national legislations in MSs for all IMPs/ CTs within the Directive as well as reporting to investigators. (ASRs are submitted in CTIS as of the CTR and SUSARs to EV database. Not all Ethics Committees might have access to EV)

In Addition the Version 2 of The Q&As contains 3 Annexes:

  • Annex I: Examples of substantial and non-substantial modifications
  • Annex II: Decision tree to establish whether a trial is a “clinical trial” (this Annex and in particular the definition for a low-interventional trial are still under discussion in the expert group on CTs)
  • Annex III: ABBREVIATIONS (Valid for Chapter 7 on Safety reporting

More information can be found in the draft CLINICAL TRIALS REGULATION (EU) NO 536/2014 - QUESTIONS & ANSWERS VERSION 2.

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