CT SOP version 1.4

Changes from:
Version 1.3: Improved wording
Version 1.2: Introducing simplified template for Annual Safety Report

The sponsor has overall responsibility for ensuring that this SOP is followed.

The sponsor’s responsibilities shall be described in the quality system of the sponsor institution. Tasks are delegated according to SOP Roles and Responsibilities in clinical trials implemented in the institution.

While the trial is in progress, principal investigators at each centre should continuously record adverse events (AE) according to the current legislation and procedures described in the protocol, and report serious adverse events to the sponsor.

The sponsor is responsible for assessing whether serious adverse events (SAE) are considered suspected unexpected serious adverse reactions (SUSARs), the submission of SUSARs to applicable authorities and informing all participating principal investigators about unexpected serious adverse reactions. The sponsor is also responsible for continuous monitoring of the safety in the clinical trial and annual safety reporting to applicable authorities.

The individual health institution in Norway has the responsibility to report events that cause significant personal injury to a trial subject as a result of a medical procedure or other causes of harm to a trial subject. Such incidents must be reported to the Norwegian Board of Health Supervision (Statens helsetilsyn). Events that could
have led to significant injury should also be reported.

The medical monitor will be delegated the sponsor tasks described in this SOP but is expected to have a close dialog with coordinating investigator (CI).

The sponsor may also transfer any or all of the sponsor’s trial-related duties and functions to a third-party vendor such as a Clinical Trial Unit or a Contract Research Organisation (CRO), but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf. Transfer of duties shall be specified in a written agreement.

A Clinical Trial Unit will only be able to enter completed SUSAR reports into Eudravigilance (EV).

AE recording

AEs, including SAEs, should be recorded from the time the informed consent form is signed until the end of the trial, unless otherwise provided for in the protocol.

PI must record all AEs in the CRF. In determining whether an AE is an adverse reaction, consideration shall be given to whether there is a reasonable possibility of establishing a causal relationship between the event and the investigational medicinal product (IMP).

PI should record all reports of exposure during pregnancy (if not allowed by the protocol), medication errors, misuse or abuse in relation to the IMP and notify the sponsor of the protocol deviation. It is recommended to have short reporting timelines for these kind of events (e.g. 24 hours).

SAE reporting to sponsor

If the AE is serious (i.e. an SAE), the PI shall within 24 hours report the event to the medical monitor of the sponsor, unless the protocol does not require expedited reporting of the SAE. Non-expeditable SAEs are recorded and notified to the sponsor per protocol.

Severity is not to be confused with seriousness. Severity refers to the intensity of the event whereas seriousness refers to the outcome or action criteria.

Serious adverse reactions (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.

SAE evaluation by sponsor

The sponsor can rely on the causality assessment made by the reporting investigator or make an additional assessment. The sponsor cannot downgrade the investigator’s causality assessment, but can upgrade it.

Expectedness of the SAE should be assessed by the medical monitor using the agreed reference safety information (investigator’s brochure or SmPC) specified in the application to authorities. When assessing expectedness of a known, already documented serious adverse reaction term, consideration will be given to information on the specificity, frequency, or severity of the reaction. Fatal SARs should usually be considered unexpected, even if previous fatal SARs have occurred.

If the SAE is considered related to the IMP and is also unexpected (suspected unexpected serious adverse reaction, SUSAR) the event must be reported to the authorities. In the European Economic Area (EEA), that requirement is met by entering the SUSAR in EV, see Reporting to Authorities below.

The reference safety information (RSI) in effect and approved at the time of occurrence of the ‘suspected’ SAR should be used to assess expectedness for follow up reports to Eudravigilance (EV) too. SUSARs should not be downgraded in EV on the basis that the RSI was updated after the occurrence of the event.

SUSAR reporting and dissemination

Minimum information for SUSARs

The initial SUSAR report must contain at least the following information:

• Valid EU CT number.
• One identifiable coded subject.
• One identifiable reporter.
• One SUSAR.
• One suspect IMP.

In addition, it is recommended that the following information is provided:

• A full description of the event (or if all the information is not available at the time of the initial report, this could be included in the follow-up), including the event start date, whether it is resolved or not and, if resolved, the date of resolution.
• Any relevant medical history or relevant concurrent conditions that are not already listed as part of the event.
• An assessment of seriousness and expectedness.
• Dates that the suspected drug was administered to the subject, and whether any changes to administration have been made because of the event (such as ceasing the medication or changing the dose).
• Details of any concomitant medications.
• In the case of death, the date and cause of death.
• Receipt date of the information from the investigator.
• Whether the report is an initial report or a follow-up report

Reports should comply with the health facility’s privacy policy.

Reporting to Authorities

The medical monitor should send the SUSAR information on Individual Case Report Form Eudravigilance - Template or other equivalent form to the EV user at SUSAR@ous-hf.no for Helse Sør-øst and Helse Nord, similarly SUSAR@helse-bergen.no for Helse Vest and Helse Midt if no local solution is available. It is the medical monitor’s responsibility to ensure that the form is complete.

In EEA, fatal or life-threatening SUSARs should be reported to the Eudravigilance database within 7 days of receipt by the medical monitor, and with follow-up information reported within 8 days, whereas all other SUSARs are to be reported within 15 days.

In order to reach the timelines, the medical monitor should inform the EV user as soon as possible that a SUSAR is to be reported and send the Individual Case Report Form Eudravigilance - Template or equivalent within 72 h (day 3) after the sponsor has gained knowledge of the SAE if the seriousness criteria is death or life-threatening or within 10 calendar days after the sponsor has gained knowledge of the SAE for other seriousness criteria.

If any of the participating countries are outside the EEA, submission should be performed as outlined in the Safety Reporting Specifics - Template for the study.

Only unblinded reports should be submitted, so for blinded trials the medical monitor must be independent of the operational study team and be careful not to share unblinded information with study staff.

SUSARs associated with comparators follow the same reporting requirements as for the test IMP. Events associated with placebos will usually not satisfy the criteria for a SUSAR and, therefore, neither for expedited reporting. However, where SUSARs are associated with placebos (e.g., reaction due to an excipient or impurity), the sponsor should report such cases.

For reports of deaths or SAEs also considered efficacy endpoints in trials with high mortality or high morbidity and accepted to be considered as disease-related events in the protocol authorised by the competent authorities; systematic unblinding is not required.

Careful assessment should be performed in cases where disease-related events appear to be enhanced by the IMP. If the investigator considers a disease-related event to also be IMP-related and the event is both serious and unexpected then it must be reported as a SUSAR.

In trials with several IMPs, an adverse reaction (AR) must be “expected” for all suspected IMPs (according to the separate RSIs) for the SAR not to be considered as a SUSAR.

Reporting to collaborating investigators

The medical monitor shall inform all investigators about all SUSARs. Individual SUSAR reports can be distributed. However, whenever practicable, the information on SUSARs should be aggregated in a line listing of SUSARs in periods as warranted by the nature of the trial and the volume of SUSARs generated. This line listing should be accompanied by an updated benefit-risk evaluation and risk mitigation measures. All principal investigators must confirm receipt of and acquaintance with the new SUSARs.

Unexpected events and urgent safety measures

In addition to SUSARs, all unexpected events that might materially influence the risk-benefit assessment of the IMP or that would lead to changes in the administration of an IMP or in overall conduct of a clinical trial, must be submitted to the Authorities. Unexpected events include an increase in the rate of occurrence of expected serious adverse reactions which may be clinically important, a significant hazard to the patient population, such as lack of efficacy of a medicinal product, or a major safety finding from a newly completed animal study (such as carcinogenicity).

Where an unexpected event is likely to seriously affect the benefit-risk balance, the medical monitor and the investigator shall take appropriate urgent safety measures to protect the subjects. The information should be provided to CI for reporting to authorities.

The CI must report all unexpected events through CTIS to the authorities of the country (or countries) concerned without undue delay, and at the latest within 15 days. Any urgent safety measures taken must be reported through CTIS without undue delay, and at the latest within 7 days after measures have been taken.

Reporting of pregnancies

Pregnancies should be reported by the PI to the sponsor within the timelines and reporting lines as described under AE recording farther up. As much information as possible should be gathered about the expecting mother and her baby. The mother and the baby should be followed for at least three months after delivery, if possible, provided consent for collection of data is given. Information about a pregnant partner can only be collected upon consent from the partner. If a pregnancy has an adverse outcome (i.e. for the mother and/or the baby), an SAE report must be completed. Information about the baby can only be collected upon consent from the parents (guardians).

Annual Safety Report

In the EEA, non-commercial sponsors may use the Simplified Template of Annual Safety Report (ASR) on IMPs with a marketing authorisation holder in any of the EU/EEA member states and when the RSI is the SmPC.

All RSIs in effect during the reporting period must be included with the ASR submission.

ASRs should always be written in English.

IMP refers to an active substance in the context of ASRs, not placebo.

Submission of ASR is not required in drug trials with short overall duration, less than 12 months from study start to end of trial.

The ASR is expected to contain interval line listings of the serious adverse reactions (SARs) and a cumulative summary of serious adverse events (SAEs). In addition, ASRs will also contain a list of deceased trial participants and participants who dropped out in association with an AE. SARs in the line listing should be recorded with case ID and study ID without including subject ID in this document.

The line listings of SARs should use the RSI in effect at the start of the annual reporting period.

If necessary, relevant safety information on auxiliary medicinal products (AxMPs) similar to the reference compound should be addressed in the ASR of the IMP.

If feasible, the sponsor should also calculate patient-years of treatment. This information may be especially useful in the interpretation of data when there are substantial differences in time of exposure between subjects randomised to the tested product and comparator(s).

For ASR reporting purposes, see also Changes in RSI below.

For trials where a pharmaceutical company includes the trial safety information in their Development Safety Update Report (DSUR), the medical monitor should request confirmation from the company that all trial information really has been included.

Changes in RSI

If a new RSI is expected to be used for the next ASR reporting, the current RSI used to identify SUSARs in the ASR should be submitted with the ASR, as well as the proposed new RSI, and any changes to the RSI should be detailed in the ‘Changes to the Reference Safety Information’ section of the ASR.

An RSI update (e.g. addition of new expected SAR preferred terms (PTs), change of the frequency of expected SARs, MedDRA updates having an impact on the PTs listed in the RSI, etc.), as well as an update of section 4.8 of an SmPC when it is used as an RSI, is always a substantial modification.

Whenever the RSI is changed, the CI should consult with the medical monitor and
evaluate whether the protocol and/or the informed consent document should be updated.

Upon submission of an IB in a substantial modification application containing an update to the RSI, which is not accompanied by a protocol modification, the sponsor should specify in the submission cover letter what risk mitigation measures are already in place in the protocol to manage any new safety issues and if these new
safety issues are adequately covered in the subject information leaflet (informed consent form), or if it needs to be updated.

If the RSI is in section 4.8 of the SmPC and a new public version of the SmPC with an updated section 4.8 becomes available during the trial, it is recommended to submit a substantial modification requesting approval of the update to the RSI immediately. Following approval of the SmPC for use as RSI in at least one member state concerned (MSC) with the ongoing clinical trial, the updated SmPC should be used for the purposes of expedited reporting.

Reporting overview

*For blinded trials, reporting should be delegated to an independent, qualified person. Randomisation, Blinding and Unblinding - SOP 1.2.b.
**Sponsor should immediately take appropriate safety measures to prevent injury to subjects.

• Individual Case Report Form Eudravigilance - Template
• Safety Reporting Specifics - Template
• Protocol Deviation Handling Plan - Template
• Simplified Template of Annual Safety Report (ASR)