Reporting requirements for ongoing Clinical Trials after approval

Definitions

Adverse Event (AE)

An AE is any untoward medical occurrence in a study participant to whom a medicinal product is administered, and which does not necessarily have a causal relationship with the medicinal product.  

An AE can be any unfavourable and unintended sign (including, for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

Adverse Reaction (ARs) / Adverse drug reactions (ADRs)

  An AR/ADR is any noxious and unintended response to a medicinal product related to any dose of the product that has at least a reasonable possibility of a causal relationship between the medicinal product and the AE. In accordance with ICH E2A, a reasonable possibility implies that  the relationship cannot be ruled out.  

Serious Adverse Event (SAE)

A SAE is defined as any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. However, it does not necessarily imply a causal relationship with the medicinal product.

Serious Adverse Reaction (SAR)

A SAR is defined as any noxious and unintended response to a medicinal product related to any dose administered that result in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. A SAR, in contrast to a SAE, implies at least a reasonable possibility of a causal relationship between the medicinal product and the SAE.

Suspected Unexpected Serious Adverse Reaction (SUSAR)

A SUSAR, is a SAR where “unexpected serious adverse reaction” refers to a SAR that in terms of type, severity or outcome, does not align with the “Reference Safety information” (RSI).  The RSI is either a specifically designated section in the Investigator’s Brochure (IB) or section 4.8 of the Summary of Product Characteristics (SmPC) for a marketed product.

Early trial termination (ET)

An ET refers to the premature end of a clinical trial due to any reason before the conditions specified in the protocol are complied with. An earlier end of a clinical trial which is based on faster recruitment than anticipated, should not be considered as an "early termination''.

Serious breach (SB)

A SB means a breach of the clinical trial regulation or the approved version of the clinical trial protocol that is likely to affect to a significant degree the safety and rights of a trial participant or the reliability and robustness of the data generated in the clinical trial.

Temporary halt (TH)

A TH means an interruption of the conduct of a clinical trial by the Sponsor that was not provided in the protocol with the intention of the Sponsor to resume it. The TH may be due to causes that affect or do not affect safety and/or the benefit-risk balance.

Unexpected Events (UE)

UEs are events that affect the benefit-risk balance in a clinical study. Examples of such unexpected events include a clinically significant increase in the frequency of expected SARs that may be of clinical importance, a significant risk to the patient population, such as lack of effectiveness of a drug, or a major safety finding from a recently completed animal study (e.g., carcinogenic properties).

Urgent Safety Measure (USM)

USMs are urgent safety measures implemented to protect clinical trial participants in response to an unexpected event that is likely to significantly affect the benefit-risk balance of the study.

Reporting of notifications connected to the conduct of a clinical trial, that do not affect the benefit-risk balance  

  According to Chapter VI, Articles 36 and 37 of the clinical trial Regulation (EU) 536/2014, the Sponsor is required to notify each  Member State concerned of certain events affecting the conduct of a clinical trial within 15 days of the event occurring. These events include:

• Start of the clinical trial (Art 36)
• Start and end of recruitment of study participants (Art 36)
• Temporary halt of a clinical trial for reasons not affecting the benefit-risk balance and subsequent restart of the clinical trial (Art 37). A temporary halt notification should be accompanied by an end of recruitment notification, which should be submitted beforehand.
• Early termination of a clinical trial for reasons not affecting the benefit-risk balance (Art 37)
• End of a clinical trial (Art 37)

In a multinational clinical trial, notifications must be submitted separately to each Member State concerned. Notifications covered by Art 37 must include a justification and, where applicable, a description of any follow-up measures for study participants.

In clinical trials, where the clinical trial protocol provides for an intermediate data analysis date prior to the end of the clinical trial, and the respective results of the clinical trial are available, a summary of those results shall be submitted to CTIS within one year of the intermediate data analysis date, as per Article 37 (8).

Please note that the authorisation of a clinical trial will expire if no study participant is  recruited within 2 years of approval.

Please also note that a trial that is temporarily halted and not restarted within two years will be considered terminated. If the sponsor expects the trial to resume after this two-year period, a substantial modification (SM) may be submitted before the end of that period, requesting a restart date after the two years have elapsed. This approach is applicable  to both temporary halts for reasons affecting the benefit-risk balance or not.  

Reporting of notifications connected to events not anticipated in the protocol, affecting the benefit-risk balance (safety and other)

In accordance with Chapter VI, Articles 38, 52, 53, and 54 of the clinical trial Regulation (EU) 536/2014, the Sponsor is required to notify the Member States concerned of certain events that impact the benefit-risk balance, the rights and safety of trial participants and/or the data quality of the clinical trial within specific deadlines after the event occurred. These events include:

• Temporary halt for reasons affecting the benefit-risk balance (Art 38), accompanied by an end of recruitment notification.
• Early termination of a clinical trial for reasons affecting the benefit-risk balance, i.e., considerations for participant safety and/or lack of efficacy (Art 38)
• Serious breach likely to significantly affect the safety and rights of trial participants, and/or the reliability and robustness of data generated in the clinical trial (Art 52)
• Unexpected event impacting the benefit-risk balance in a clinical trial that were not foreseen (Art 53)
• Urgent safety measures implemented to protect trial participants, in response to an unexpected event that is likely to have a serious impact on the benefit-risk balance of the clinical trial (Art 54)

Reporting of temporary halts and early termination of a clinical trial for reasons affecting the benefit-risk balance (Art 38), the following applies:

In cases where the Sponsor has initiated a temporary halt or an early termination of a clinical trial for reasons that affect participants’ safety and/or the benefit-risk balance, the Sponsor must immediately, but not later than 15 days after the event, notify the Member States concerned via CTIS. The notification should provide information of the underlying reasons for the action, the number of subjects included in the study, the number of subjects under treatment and the number of subjects under follow-up in each Member State concerned.  It should also describe follow-up measures for the trial participants, including potential treatment options after the TH or ET and provide a confirmation that the investigators and trial participants have been adequately informed of the Sponsor’s decision.  

Resuming a clinical trial that was halted for reasons of safety requires the submission and approval of a substantial modification. The Sponsor must include a justification for the restart, including  conclusions of the analysis, the mitigation measures if applicable and an updated benefit/risk assessment.

Please note that notifications concerning safety related notifications can only be submitted to Members States concerned in which the clinical trial has been initiated and/or is not halted.  If the same measure (i.e. TH and UE) also applies to the other Member States concerned in the multinational trial where the trial status does not allow submission, the sponsor shall inform the RMS (or any other Member State concerned where the notification can be submitted) about which of the country is affected via the notification supporting document. This should include a commitment to apply the same measures in case the trail is initiated/ restarted prior to the issue being resolved.

For additional information and technical guidance, please refer to the CTIS Sponsor Handbook, CTIS structured data form – Notifications and Results and Chapter 10 of the Clinical trial Regulation (EU) 536/2014 Q&A guidance document

Reporting of Serious Breaches (Art 52)

Investigators and other service providers should immediately report potential serious breaches to the Sponsor; this is important to ensure that the Sponsor can conduct further investigations into the breach and assess whether the breach qualifies as a serious breach.

It is essential to emphasize that, even if measures were taken to prevent similar serious breaches, the serious breach has already occurred, and legal obligations must be fulfilled. For example, a systematic and/or significant dosing error should be classified as a serious breach, regardless of whether the study participant experienced any adverse effects as a result of the error. Such serious breaches must be reported via CTIS accordingly.

It is the Sponsor's responsibility to investigate and identify the root cause of the serious breach and assess its impact on the safety and/or the rights of the clinical trial participants, as well as the reliability and robustness of the data.

Serious breaches must be reported by the Sponsor via CTIS without undue delay, but no later than 7 days after the Sponsor became aware of the breach. If a serious breach identified at a clinical trial site outside the EU/EEA site is likely to affect the safety and rights of subjects in the EU/EEA and/or the reliability and robustness of the clinical trial data, then this breach requires notification to the EU/EEA.

Please note that upon completion of the clinical trial, all serious breaches should be included in the clinical study report.

The GCP Inspectors Working Group at EMA and ICH-IWG have developed guidelines on what constitutes a serious breach and its reporting requirements. Please refer to the “Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol.” . Annex I of this guideline includes examples of what constitutes serious breaches and what should not be classified as such. For further guidance on the submission of serious breach notifications, see the CTIS Sponsor Handbook and CTIS structured data form – Notifications and Results.

Reporting of Unexpected Events

To ensure the safety of clinical trial participants, it is crucial that all affected Member States are notified of any unexpected event that may have a significant impact on the benefit-risk assessment of the medicinal product, that would lead to changes in the administration of the medicinal product or alter the overall conduct of the clinical trial. -

If an unexpected event arises that affects the benefit-risk balance of a clinical trial but is not considered a SUSAR, the Sponsor must notify the affected Member States by submitting a notification via CTIS without undue delay but no later than 15 days from the date the Sponsor became aware of the event.

Please note that SUSARs are unexpected events, but are not subject to unexpected event reporting requirements, as specific reporting requirements apply to SUSARs (see CTR Art. 42).

For further details on the reporting of unexpected events and technical guidance, refer to the CTIS Sponsor Handbook and CTIS structured data form – Notifications and Results.

Reporting of Urgent Safety Measures

If an unexpected event affects the benefit-risk balance of a clinical trial, the Sponsor and responsible investigator must implement appropriate safety measures to protect study participants. Such safety measures can be implemented without prior approval.

However, the Sponsor must notify the Member States of the event and the measures taken via CTIS without undue delay, but no later than 7 days from the date the measures were implemented. After the urgent safety measures have been implemented, all relevant trial documentation needs to be updated and submitted as a substantial modification for approval.

Urgent safety measures may involve a temporary halt of the clinical trial due to safety reasons. In such cases, it is not necessary to submit both an urgent safety measure and a temporary halt notification, but a single notification is sufficient. If the entire clinical trial is halted (recruitment and/or treatment), a temporary halt notification should be submitted. However, if only parts of the trial are halted (e.g. certain treatment arms, treatment groups or subprotocols), this should be reported as urgent safety measure to ensure that the overall trial status as ongoing is correctly reflected in CTIS.

There may be cases where a clinical trial is ended earlier for reasons of lack of efficacy or for reasons related to lack of/insufficient quality of the IMP. Both cases would impact the benefit-risk balance and are to be understood as a safety issue. In such cases, the decision to early terminate the clinical trial should be communicated to the Member States concerned via an urgent safety measure notification.

For further guidance on notifications of urgent safety measures in CTIS, refer to the CTIS Sponsor Handbook and CTIS structured data form – Notifications and Results and Chapter 10 in the Clinical trial Regulation (EU) 536/2014 Q&A guidance document.

SUSAR Reporting

SUSAR reporting must comply with Regulation (EU) No. 536/2014, Article 42 and Annex III. For further details, refer to the Question and Answers Document – Regulation (EU) 536/2014, Chapter 7.

SUSARs occurring during the conduct of a clinical trial must be reported as individual case reports (one report per patient) directly via the EudraVigilance Clinical Trial Module (EVCTM). Any SUSAR discovered or brought to the Sponsor's attention after the study has been completed must also be reported to EVCTM.

In case the specificity or severity of an expected SAR changes, this SAR should be considered unexpected and must be reported as SUSAR via the EVCTM.

Please be aware that NOMA no longer accepts the submission of SUSAR reports via CIOMS forms and that the Sponsor is responsible for submitting all SUSARs directly to the EVCTM.

Note that comparators and placebos are considered Investigational Medicinal Products (IMPs). As a result, SUSARs related to comparators and placebos are subject to the same reporting requirements as SUSARs for the test IMP. While events associated with placebo generally do not meet the criteria for a SUSAR and are therefore not reportable to EudraVigilance, any SUSAR linked to a placebo (e.g., a reaction caused by an excipient or impurity) should be reported as SUSAR by the Sponsor. The Sponsor should implement appropriate risk-minimisation measures in these cases.

In cases were a SUSAR is linked to a comparator, the Sponsor is recommended to inform the marketing authorization holder of the comparator product of the SUSAR.

Only unblinded SUSARs should be reported to EudraVigilance. In blinded trials it is therefore crucial that the Sponsor has appropriate procedures in place to ensure that unblinded information is accessible exclusively to individuals involved in safety evaluation and reporting to EudraVigilance. The blind must be maintained for individuals responsible for the conduct of the clinical trial, including management, monitors, investigators, and those responsible for data analysis and interpretation of results at the end of the clinical trial.

Deadlines for reporting of SUSARs are as follows:

• For fatal or life-threatening SUSARs: as soon as possible and no later than 7 days after the Sponsor becomes aware of the reaction.
  • If the initial report was incomplete, the Sponsor must submit a complete report, based on the initial report, within 8 days thereafter.
• For non-fatal or non-life-threatening SUSARs: within 15 days after the Sponsor becomes aware of the reaction.
• If a SUSAR was initially considered to be non-fatal or non-life-threatening but later turned out to be fatal or life-threatening, the event must be reported as soon as possible, but no later than 7 days after the Sponsor became aware of the reaction being fatal or life-threatening.

When, after the initial report, it is considered that an event no longer fulfils the SUSAR reporting criteria, for example upon receiving follow-up information from the investigator leading to a change of causality (from Related to Not Related), seriousness (from Serious to Non-Serious), or expectedness (from Unexpected to Expected) a follow up report downgrading the SUSAR should be sent. A change in expectedness can only lead to a downgrade if the investigator changes the diagnosis, but not because of an update to the Reference Safety Information (RSI) (compared to the RSI at time of SUSAR). A sponsor shall never downgrade a report, even when they disagree with the investigator’s assessment. The opinions of both the investigator and the sponsor should be provided in the narrative and in the relevant structured ICH E2B data elements.

The Sponsor should immediately notify all affected investigators/institutions of findings that may negatively impact the safety of trial participants and should expedite the reporting of all SUSARs to all affected investigators/institutions (see ICH E6). The primary focus should be on informing investigators about changes to the safety profile, rather than individual SUSAR reports. For example, information derived from SUSAR reports can be communicated via a “Dear Investigator letter”, which include both an updated benefit-risk assessment and appropriate risk minimization measures. Safety information provided to investigators should be concise and practical. Whenever possible, information to the investigators/institutions should at least include a list of SUSARs that have occurred in the relevant Member State, along with a summary of the evolving knowledge of the safety profile of the medicinal product and an updated benefit-risk assessment for the ongoing clinical trials.

Annual Safety Report (ASR)

ASRs, previously referred to as DSURs, should provide a comprehensive annual review and evaluation of relevant safety information related to an active substance under investigation. The maximum reporting period for an ASR must not exceed 1 year.  

ASRs should primarily be prepared and submitted at the active substance level. Fixed combination products may be submitted in a joint annual report. Exceptionally, for example for academic trials, an ASR may be submitted at the clinical trial level instead of at the active substance level.

ASRs must comply with the ICH E2F guideline.

ASRs shall be submitted via CTIS from the authorisation of the first clinical trial in any EU/EEA Member State until the end of the last clinical trial conducted by the Sponsor with the IMP in any EU/EEA Member State.

When submitting an ASR, the Sponsor should indicate the relevant Member States where a clinical trial is still ongoing. In cases where all trials with the IMP have been on hold for over 1 year, the Sponsor may opt to submit a simplified ASR.

Please note that the requirement for submitting an ASR also applies to IMPs included in Phase IV clinical trials, low-intervention clinical trials, and long-term follow-up studies. Only single short clinical trials with a duration of less than one year do not require the submission of an ASR.

The start of the ASR reporting period is typically the date of the Sponsor’s first authorisation to conduct a clinical trial with the IMP in any country worldwide, also referred to as the Development International Birth Date (DIBD). The end of the reporting period, referred to as the “Data Lock Point”, is the last day of the one-year reporting period. If the Sponsor prefers, the “Data Lock Point” may instead be set as the last day of the DIBD month.

ASRs must be submitted in CTIS within 60 days after the “Data Lock Point”.

For further guidance on the submission of annual reports in CTIS, please refer to the CTIS Sponsor Handbook.

For non-commercial Sponsors using an IMP with a marketing authorization, where the DIBD is unknown, the date of approval of the first clinical trial with this IMP by the Sponsor will serve as the start date for the ASR reporting period.

For non-commercial Sponsors conducting a single clinical trial using IMPs with a marketing authorization in any of the EU/EEA Member States and where the SmPC (section 4.8) is used as the Reference Safety Information (RSI), submitting a simplified ASR based on the “Simplified Template of Annual Safety Report” available via the CTCG website is strongly recommended. This template provides detailed instructions on the information expected to be included in the ASR and the information that can be omitted in this context. Using the template ensures compliance with the ICH E2F guideline.

All ASRs must be written and submitted in English, regardless of whether the ASR is submitted to one or multiple Member States.

For additional information on submitting ASRs via CTIS, please refer to CTIS Sponsor Handbook.

Relevant Resources

• Clinical trial regulation (EU) No. 536/2014
• ICH-E2F guideline (external link) 
• Questions and Answers Document - Regulation (EU) 536/2014
• EudraVigilance training and support
• Clinical Trials Coordination Group (CTCG)
• Reporting requirements under the Clinical Trials Regulation (EMA website)  
• CTIS Sponsor Handbook (PDF)  
• Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol