CT SOP version no 1.1.

Main changes from version 1.0: Annual report start dates included, IMP safety information update.

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

The sponsor is responsible for appointing medical monitors. The medical monitors assess the safety aspects of the clinical trial. The coordinating investigator (CI) can take on the role as a medical monitor if the trial is not blinded. For trials where CI should be blinded, the medical monitor role should be given to people who can be
unblinded. The medical monitors should always have a close dialogue with CI.

CI is anticipated to assume the coordinating activities on behalf of the sponsor according to this SOP. CI will appoint the medical monitors and ensure that a complete oversight of clinical trial requirements is obtained for the applicable participating countries/sites. CI is responsible for outlining the safety reporting requirements for the clinical trial and ensure that the reporting requirements can be fulfilled via EudraVigilance (EV) notifications for EEA or via local/national databases/notification systems outside EEA.

The sponsor may transfer any or all of the sponsor's trial-related duties and functions to a third party vendor such as a Clinical Trial Unit (CTU) 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.

EV reporting of Suspected unexpected serious adverse reactions (SUSARs) can be delegated by the sponsor to e.g. Oslo University Hospital or Helse Bergen. A Data Processing Agreement (DPA) between the sponsor institution and the organisation entering the SUSAR into EV is required. The medical responsibility remains with
the sponsor.

Safety planning

Risk adaptations to safety reporting should be considered. Areas that may be considered are:

• Non-serious adverse events, reduced or no collection.
• Reduced lab. monitoring.
• Physical examination and vital sign collection, may not need to be collected or reduced collection.
• Once concomitant medication use is documented at baseline, changes in concomitant therapies (e.g., changes in dose, added therapies, discontinuation of therapies) may not need to be collected.

Any exemption from standard AE/SAE reporting should be clearly stated and justified in the protocol. Please refer to Chapter 4.2 in Risk proportionate approaches in clinical trials and A selective approach to safety data collection in specific late-stage pre-approval or post-approval clinical trials, ICH E19.

The CI should ensure his/her institution has the possibility to report SUSARs in EV or has a DPA with an institution that can see overview at norcrin.no over which institutions that have a DPA in place.

Preparations for Safety Reporting

Safety Reporting Specifics - Template form should be completed, taking into account the requirements listed below.

Personnel

Medical monitor(s) with responsibility for review and evalution of SAEs, SUSAR and annual safety reporting should be appointed for the study.

It is recommended that the medical monitor role is shared between several people to ensure that at least one person is available at all times. For blinded trials, the medical monitor should not be involved with recruitment and treatment of study subjects, as they might become unblinded when reporting SUSARs or emergency unblinding.

Medical monitors may also be involved in unblinding of investigational medicinal products (IMP) in emergency situations. Both for this task and for reporting of SUSARs, the medical monitor should have access to unblinding.

A data manager might be able to provide listings and tables for information to investigators and annual safety reports to authorities.

For international trials, including non-EEA countries, the CI should collect information about local requirements.

Reference safety information

The reference safety information (RSI) should contain a list of expected serious adverse reactions (SARs) and their frequencies. For authorised products, the Summary of Product Characteristics (SmPC) will usually be the RSI. If the use of the IMP in the trial is outside the approved product indication, the CI should justify the use of the SmPC in the cover letter and if applicable in the study protocol. For unauthorised products, a specified section in the Investigator’s Brochure (IB) will be the RSI. The RSI may be specific to an indication. For authorised products that have been newly approved and where sponsor has a collaboration with the marketing authorisation holder (MAH), e.g. the MAH provides the IMP, the CI may consider using the IB to have updated knowledge about the IMP, but it is recommended to have the SmPC as RSI document may change during the course of the study.

Reconciliation

For studies where the SAE information is entered into an additional database (e.g. industry cooperation) to the trial data, the frequency of the SAE reconciliation should be specified, see also Data Management - SOP 1.12.b.

Define start date for annual safety reporting

The start date for collection of data for the annual safety reporting must be defined. The Annual Safety Report (ASR) period should never be longer than 1 year. The report will include data from study start to end of reporting period.

For trials using IMPs with a marketing authorization holder in any EEA country, the approval date of the trial in CTIS can be used as collection start date.

For trials where the IMP does not have a marketing authorisation in the EEA, it is strongly recommended to contact the developer of the IMP and ask them to include the data from the trial in their Development Safety Update Report (DSUR). The start date will be the approval date for the first trial conducted by the developer of the IMP (IMP ”date of birth”).

How to keep up to date on IMP safety information

The medical monitor should have up-to-date knowledge of the IMP. New knowledge can for instance be obtained through:

• Safety information from the trial.
• Safety findings from other trials, including preclinical studies.
• Recommendations from a Data Monitoring Committee.
• Updates of the RSI.
• Newsletter from health authorities.

The medical monitor should have a plan for actively searching for new information. Important safety changes (e.g. contra-indication, special warnings, and precautions for use, interactions, undesirable effects etc.) in the SmPC (or IB, if relevant) should be checked. The frequency for checking should be risk-based. New information that warrants update of the protocol and/or the informed consent document should be submitted to authorities and investigators should be appropriately informed.

• Safety Reporting Specifics - Template
• Eudravigilance and SUSAR Reporting - Template
• Data Processing agreement SUSAR reporting - Template