CT SOP version no 2.0

Main changes from version CT SOP version no 1.1: Updated according to ICH GCP R3. Reference safety information section has been rephrased and the need for review of RSI has been added. 

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 someone who can be
unblinded (not involved as site staff). 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 safety requirements is obtained for the applicable participating countries/sites. CI is responsible for outlining the safety reporting requirements for the clinical trial and ensuring 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 service provider such as a Clinical Trial Unit (CTU) or a service provider, 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.

Sponsors may transfer EV reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) to 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
• if participating countries are outside the EEA, local requirements may apply

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

The CI should ensure that sponsor has access to report SUSARs in Eudravigilance (EV) or has a signed DPA with an institution that can report on their behalf. A list of institutions where SUSAR reporting in EV is delegated is available at NorCRIN. If the sponsor have neither of the alternatives, it might be because the sponsor does not have a responsible person registered at the European Medicines Agency (EMA). Then  The EudraVigilance Registration and SUSAR Reporting Working Instruction should be followed. 

Preparations for Safety Reporting

Personnel

Medical monitor(s) with responsibility for review and evaluation 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 participants, 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.

The data manager may 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, sponsor must provide an Investigator’s Brochure (IB)  where the RSI is included. In SOP Investigational Medicinal Product (IMP) at Trial Start additional guidance on RSI and content of the IB is provided. In some cases the IMP manufacturer might provide the IB to sponsor. 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. It is however recommended to have the SmPC as RSI document.

The RSI should be reviewed periodically (e.g. annually when preparing the ASR) and if relevant safety information becomes available sponsor must consider if the study specific RSI should be updated and submitted for approval to authorities (substantial modification in CTIS). Sponsor's review of RSI should be documented (Safety Information Review Log - Template).

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 report (ASR) is the clincial trial approval date in CTIS in any participating country.

Submission of the ASR must be no later than 60 days after the annual reporting period, and the ASR period should never be longer than 1 year. 

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 from:

• safety information from the trial
• safety findings from other trials, including preclinical studies
• recommendations from a Data Monitoring Committee
• updates of the SmPC or IB
• newsletter from health authorities

The medical monitor should have a plan for actively searching for new information. Important safety changes (e.g. contraindication, 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 outside the European Economic Area (EEA)

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

• Data Processing agreement SUSAR reporting - Template
• Safety Information review Log - Template