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Reporting requirements for ongoing Clinical Trials after approval

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    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 (AR)

    An AR is any noxious and unintended response to a medicinal product related to any dose of the product. In accordance with ICH-E2A, the definition of an adverse reaction implies at least a reasonable possibility of a causal relationship between the adverse event and the IMP, i.e. the relationship cannot be ruled out.  An AR, in contrast to an AE, implies at least a reasonable possibility of a causal relationship between the medicinal product and the SAE.

    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 responses to an IMP 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 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.

    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)

    Urgent 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 the member states concerned of certain events affecting the conduct of a clinical study 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 for reasons not affecting the benefit-risk balance and subsequent restart of the clinical trial (Art 37)
    • Early termination of a clinical for reasons not affecting the benefit-risk balance (Art 37)
    • Data from interim data analysis, if described in the protocol (Art 37, point 8)
    • End of a clinical trial (Art 37)

    In a multinational clinical trial notifications must be submitted to each concerned member state separately. Notifications covered by Art 37 must include a justification and if 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, point 8.

    Please note that the approval of a clinical trial that does not recruit any study participant within 2 years will expire.

    Please note that a study that is temporarily halted and is not restarted within 2 years will be considered terminated.

    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 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)
    • 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 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 must include a justification for the action and describe follow-up measures for the trial participants. Resuming a clinical trial that was halted for reasons of safety requires a submission and approval of a substantial modification.

    For additional information and technical guidance, refer to the CTIS Sponsor Handbook and CTIS structured data form – Notifications and Results.

    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.

    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 notification, 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. These unexpected events must be reported in addition to SARs.

    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.

    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.

    Please note that in cases where an urgent safety measure results in a temporary halt of the clinical trial due to safety reasons, both events must be reported in CTIS. The notification of the urgent safety measures must be reported prior to the temporary halt. Resuming the clinical trial after a temporary halt due to safety reasons, requires the submission and approval of a substantial modification.

    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.

    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.

    The Sponsor should immediately notify all affected investigators/institutions of findings that may negatively impact on 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 product and an updated benefit-risk assessment for the ongoing clinical trials.  

    Annual Safety Report (ASR)

    ASRs, previously known 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 should be 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. ASRs must comply with the ICH-E2F guideline.

    Exceptionally, for example for academic trials, an ASR may be submitted at the clinical trial level instead of at the active substance level.

    ASRs shall be submitted via CTIS from the start 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 relevant member states where a clinical trial is still ongoing should be indicated. 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, also known as the “Data Lock Point”, is the last day of the one-year reporting period. If the Sponsor wishes, the “Data Lock Point” can be set as the last day of the DIBD month.

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

    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 detailed information on the structure and content of an ASR, refer to the ICH-E2F guideline.

    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 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