CT SOP version 2.0

Changes from:

Version 1.4: Checked for changes in ICH GCP R3 + new RSI should be submitted within one month of ASR submission. Safety Reporting Specifics has been replaced by Safety Information Review Log. Removed internal reference to Randomisation, Blinding and Unblinding - SOP 1.2.b. Removed attachment Protocol deviation Handling Plan. Added sentence about useof DSUR template for unauthorised products. 

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
• informing all participating principal investigators about unexpected serious adverse reactions.
• continuous monitoring of the safety in the clinical trial 
• 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).

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 specified 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 IMP not allowed during pregnancy 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 occurs after the end of the trial shall be reported to the sponsor without undue delay.

SAE evaluation by sponsor

The reporting investigator shall provide a causality assessment.  If the sponsor disagrees with the investigator's causality assessment, sponsor can 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 the 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 also be used to assess expectedness for follow up reports to Eudravigilance (EV). SUSARs should not be downgraded in EV based on update of the RSI 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:

• Full description of the event (if all the information is not available at the time of the initial report, this could be included in the follow-up report), 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 drug administration have been made due to 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

For sponsors with an agreement with Oslo University Hospital HF or Helse Bergen HF regarding submission of SUSAR reports in Eudravigilance on their behalf, the medical monitor should send the SUSAR information on Individual Case Report Form Eudravigilance or other equivalent form to the respective EV-reporting units:

• SUSAR@ous-hf.no for sponsors in Helse Sør-øst and Helse Nord or to
• SUSAR@helse-bergen.no for sponsors in Helse Vest and Helse Midt.

It is the medical monitor’s responsibility to ensure that the form is complete and to update the EV-reporting units with any follow-up information to be reported.

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 or equivalent within 72 h (day 3) after the sponsor has had knowledge of the SAE if the seriousness criteria is death or life-threatening or within 10 calendar days after the sponsor has had knowledge of the SAE for other seriousness criteria.

If any of the participating countries are outside the EEA, sponsor should have oversight of reporting obligations, procedure and method. If reporting is outsourced to a service provider, an agreement specifying delegation of tasks is required. 

Only unblinded reports should be submitted.  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 assessment of expectancy should be done for each IMP according its respective RSI. If an adverse reaction (AR) is “unexpected” for at least one IMP the SAR should 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, when practically possible, 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 possible risk mitigation measures. Distributing the Annual Safety Report may be one way of informing investigators about SUSARs. 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  to the authorities of the country (or countries) concerned through CTIS, 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 above. 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 with consent from the parents (guardians).

Annual Safety Report

In the EEA, non-commercial sponsors may use the Simplified Development Safety Update Report (DSUR) for annual safety reporting on IMPs with a marketing authorisation holder in any of the EU/EEA member states and when the RSI is the SmPC.

For unauthorised products, a full DSUR should be written, DSUR can be used.

All RSIs in effect during the reporting period must be included with the annual safety report (ASR) submission.

ASRs should always be written in English.

To submit the ASR in CTIS, one must have the role "ASR submitter".

Completion of the simplified DSUR will in most cases require contribution from both CI, DM and MM.

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 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.

For the ASR, line listings of the adverse events (AE/SAE/SAR) should be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) or an equivalent medical dictionary.

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 information for the trial in question has also 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 updated, the CI should consult with the medical monitor and evaluate whether the protocol and/or the informed consent document should be updated. 

Sponsor's review of RSI should be documented (Safety Information Review Log - Template) .

When submitting an Investigator’s Brochure (IB) as part of a substantial modification application that includes an update to the Reference Safety Information (RSI) but does not involve a protocol amendment, the sponsor should clearly indicate in the cover letter:

• What risk mitigation measures are already implemented in the current protocol to address any newly identified safety concerns, and
• Whether these new safety issues are adequately reflected in the subject information leaflet (i.e., the informed consent form), or if an update to this document is required.

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 within one month of the ASR submission. 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. 
**Sponsor should immediately take appropriate safety measures to prevent injury to subjects.

• Individual Case Report Form Eudravigilance - Template
• Simplified Template of Annual Safety Report - Template (ASR)
• Safety Information Review Log - Template