Investigators and sponsors have safety reporting obligations in relation to clinical trials on medicinal products conducted in accordance with Regulation (EU) No 536/2014.
Note that safety reporting for clinical trials regulated by previous legislation, other provisions apply. Read about this at “Clinical trials – according to Directive 2001/20/EC”.
Regulation (EU) No 536/2014 (CTR) provides, among other things, definitions for:
Adverse event (AE) means any untoward medical occurrence in a subject to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment.
Serious adverse event (SAE) means any untoward medical occurrence that at any dose requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death.
Unexpected serious adverse reaction means a serious adverse reaction, the nature, severity or outcome of which is not consistent with the reference safety information.
Note that serious adverse reactions occurring with increased frequency or severity also constitute unexpected serious adverse reactions. Fatal adverse reactions are normally always considered as unexpected. The exception is medicinal products that have a marketing authorisation in the EU and list the adverse reaction in question as fatal under Section 4.8 of the Summary of Product Characteristics (SmPC).
Suspected unexpected serious adverse reaction (SUSAR). This means that the occurrence is probably related to the investigational medicinal product, but that the occurrence is unexpected.
Reporting of AEs and SAEs by the investigator to the sponsor
The investigator shall record and document all adverse events or abnormal laboratory results unless the protocol provides differently. Serious adverse events shall be reported to the sponsor without undue delay, but not later than within 24 hours of obtaining knowledge of the events.
If, after the end of the clinical trial, the investigator becomes aware of a serious adverse event with a suspected causal relationship in a subject treated by him or her, the investigator shall report the adverse event to the sponsor without undue delay.
The sponsor shall keep detailed records of all adverse events reported to it by the investigator.
Relief from adverse event recording and reporting requirements may be granted in low-intervention trials after a thorough risk analysis. The sponsor shall then specify and justify this relief in the protocol.
Reporting of SUSARs by the sponsor to the Agency
The sponsor of a clinical trial shall, without delay, report the following SUSARs to the EudraVigilance safety database:
- All SUSARs that have occurred during the clinical trial, irrespective of whether they have occurred at a clinical trial site in the Union or in a third country.
- All SUSARs related to the same active substance, regardless of pharmaceutical form or strength or indication investigated, in investigational medicinal products used in the clinical trial, occurring in a clinical trial performed exclusively in a third country, if it is sponsored
- by that sponsor, or
- by another sponsor who is either part of the same parent company as the sponsor of the clinical trial, or who, by formal agreement, develops a medicinal product jointly with the sponsor of the clinical trial.
- All SUSARs to investigational medicinal products occurring in any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after the end of the clinical trial.
- The timeliness of SUSAR reporting depends on the seriousness of the adverse reaction.
If the suspected unexpected serious adverse reaction:
- is fatal or life-threatening, reporting shall take place as soon as possible and, in any event not later than seven days after the sponsor became aware of the reaction
- is non-fatal or non-life-threatening, reporting shall take place not later than 15 days after the sponsor became aware of the reaction
- was initially considered to be non-fatal or non-life-threatening but turns out to be fatal or life-threatening, reporting shall take place as soon as possible and, in any event not later than seven days after the sponsor became aware of the reaction.
Where necessary to ensure timely reporting, the sponsor may, in accordance with Section 2.4 of Annex III to the CTR, submit an initial incomplete report followed up by a complete report.
It is the reference safety information that forms the basis for assessing whether the adverse reaction is unexpected or not. SUSARs shall be reported unblinded but the blinding shall be maintained for persons responsible for the conduct of the trial, such as the investigator.
Reporting to the EudraVigilance database requires that the sponsor or the person/organisation to whom the sponsor has delegated the SUSAR reporting is registered (as sender) in the EudraVigilance database.
For non-commercial sponsors who do not have the resources to report SUSARs directly to the EudraVigilance, the Icelandic Medicines Agency (IMA) can assist for SUSARs that occur in Iceland. In such cases, this request shall be indicated and justified in the application cover letter and the trial protocol. Please send SUSARs to the IMA in an EU-wide form available on the CIOMS website.
Note that the form should not be sent as an email attachment due to the fact that it contains sensitive personal information.
Reporting of SUSARs by the sponsor to the investigators
In cases where the trial is conducted at more than one clinical trial site, the sponsor shall inform all investigators of the SUSARs that have occurred. However, be sure to maintain blinding for investigators and others responsible for the ongoing conduct of the clinical trial, as well as for those responsible for analysing data and interpreting results after the end of the clinical trial.
During the course of the trial, the sponsor is obliged to report all adverse reactions that meet the requirements for SUSAR to the investigators. The requirements thus mean that the occurrence is probably related to the investigational medicinal product, but that the occurrence is unexpected (ICH GCP 5.17.1).
The reports must be communicated to the investigators ‘promptly’ in accordance with ICH GCP 5.16.2, 8.3.18, without further specification of time limit. No distinction is made depending on whether a SUSAR has occurred in your own country or elsewhere.
The information must be provided in a format and with an interval that is adapted to the current trial. For trials with a high volume of SUSARs, line listings may be preferred, as they can provide a better overview than a large number of individual reports. This requires the line listings to contain sufficient information for the investigator's risk assessment.
The investigators must receive the information sufficiently quickly in order to be able to take a position on whether the new information affects the subjects. For example, for early-phase trials, frequent reporting should be considered, perhaps per occurred SUSAR. A six-month interval may be acceptable for trials of products with relatively well-known safety profiles. It is not acceptable to use a fixed interval of, for example, 2, 3 or 6 months for all trials conducted by a company, but rather a risk assessment of suitable reporting measures shall be carried out per trial. It must be possible to verify at a later stage when the investigator gained access to the information.
Annual reporting by the sponsor to the Agency
For trials lasting more than one year, the sponsor shall submit a safety report via the CTIS every year (Annual Safety Report, ASR). The report shall contain aggregated and anonymised data on all investigational medicinal products, excluding placebo, used in a clinical trial conducted by the sponsor.
The obligation to submit a report each year is calculated from when a clinical trial is first authorised and then covers all trials that the sponsor conducts with that investigational medicinal product.
The safety report should be prepared in accordance with the ICH guidelines for the Development Safety Update Report (DSUR).
Non-commercial sponsors conducting a single clinical trial on IMPs with a MAH in any of the EU/EEA member states and where the SmPC is used as RSI can use a simplified ASR template. The information should always be in English. The template is found on CTCGs website. Go to "Key documents list" and scroll down to the headline “Clinical Trials Safety”.
Other reporting obligations
A serious breach is a breach of the EU Regulation or applicable trial protocol that is likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial. The sponsor shall report serious breaches via the CTIS without undue delay, no later than seven days of the sponsor becoming aware of the breach.
For non-compliances that the sponsor considers non-serious, and therefore does not report as above, these non-compliances shall be documented in the trial documentation of the investigator and sponsor, and appropriate action shall be taken. The deviations shall be addressed in the clinical study report.
The sponsor shall notify the Member States concerned, via the CTIS, of all unexpected events that affect the benefit-risk balance of a clinical trial, but which are not suspected unexpected serious adverse reactions. This shall be done without undue delay, but no later than 15 days after the sponsor became aware of this event.
Urgent safety measures
Where an unexpected event is likely to seriously affect the benefit-risk balance, the sponsor and the investigator shall take appropriate urgent safety measures to protect the subjects. The sponsor shall notify the Member States concerned, via the CTIS, without undue delay, but no later than seven days after the measures have been taken.
In a double-blind clinical trial, it is important that the investigator has immediate access to and can break the code of an individual subject if knowledge of the actual treatment is necessary for the continued care of the subject. Processes for dealing with such situations shall be in place and be described in the protocol. The sponsor must not obstruct or delay the investigator’s code-breaking.
Auxiliary medicinal products
Safety reporting for auxiliary medicinal products already on the market shall be carried out in accordance with Chapter 3 of Title IX of Directive 2001/83/EC.
See also the recommendations of the EMA expert group available on the Commission’s EudraLex website. Click ”Set of documents applicable to clinical trials authorised under Regulation (EU) No 536/2014”. Chapter III, Auxiliary Medicinal Products in Clinical Trials.