CT SOP version 2.0

Minor changes from version 1.4 to adapt to the wording used in ICH GCP R3.  

Updated links to attachments and references.

Added details for required information about scope and reason for amendment in structured fields.

CT SOP version 1.4.

Added reference to Part II additions in first SM after transition. Replaced Norcrin templates for cover letter and SM description with CTCG templates, and updated link to CTCG Best practice guide.

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.

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

The coordinating investigator (CI) has the responsibility for ensuring that all protocol modifications are documented, and that substantial modifications are submitted through the Clinical Trial Information system (CTIS) and approved before implementation.

The CI is responsible for ensuring that the protocol is adequate, especially the risk-benefit information, and if necessary, modifying the protocol or stopping the trial. This involves an assessment of:

• any required changes
• affected documents (protocol, subject information and consent forms, CRF, IB, etc.)
• whether or not the modifications are considered to be substantial or non-substantial

Modifications may relate to the trial conduct, design, methodology, investigational or auxiliary medicinal product, participating investigators or clinical trial sites.

Modifications that have substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial, should be submitted to the competent authorities and/or ethics committees for approval.

If new circumstances or information arise regarding a clinical trial or investigational medicinal product (IMP) that could influence subject safety (risk-benefit balance), the CI will immediately take appropriate urgent safety measures to prevent injury to the participants, without awaiting prior authorisation. For multicentre trials, this is done in collaboration with the principal investigators (PIs). The CI should ensure that the authorities are notified immediately through CTIS about any changes and implemented measures. Where unexpected events require a temporary halt of the clinical trial, the CI should apply for a substantial modification before restarting the clinical trial, ref.EU Reg 536/2014article 38.

A modification to a trial can either be substantial (SM) or non-substantial (NSM). SM should always be submitted in CTIS for approval, whereas NSM should be implemented after revision of affected documents. Version date and number of revised documents must be be updated, and documents should be filed in the TMF/ISF. However, NSM that are relevant for the supervision of the clinical trial by the authorities concerned should be submitted in CTIS and are referred to as 81.9 NSM. Further clarifications and classification of SM, NSM and 81.9 NSM are described in the EU Q&A document, Annex III.

In general terms, an SM is defined as a change to any aspect of a clinical trial which is likely to have a substantial impact on:

• The safety or rights of the subjects.
• The reliability and robustness of the data generated in the clinical trial.

The application documentation for SM is described in Annex II of EU Regulation 536/2014.

There is no fee for applications in Norway for non-commercial sponsors.

It is worth noting that a change in principal investigator at a clinical trial site is considered an SM.

To create an SM, click “CREATE” in the upper right corner and select type of modification. Single trial substantial modification will apply to most academic trials. The option "Multi trial substantial modification" applies only if sponsor performs multiple studies on the same IMP in parallel.

Please refer to the SOP Application Process, Approvals, section Application Process → Responses to RFIs, for guidance on how to complete the application and respond to RFIs.

The EMA Modification description - Template and Cover letter SM - Template should be used.

If a revised document is to be submitted, a clean version should be uploaded in CTIS using the “update” function for the applicable document. The track change version of the document should be uploaded in the same way over the previous track change document if available. If only a clean document has been submitted earlier, the document with tracked changes should be added to the clean document using the “add” function.

In addition, the following should be specified in the cover letter:

• If applicable, change in source country for IMPs/AxMPs without marketing authorization in the EEA should be described (see Annex V in Q&A document).
• When submitting a substantial modification that involves an IB or SmPC (delete the section if not applicable):
  • Specify if the RSI is being updated or not and refer to the section within the document where the reference safety information (Investigator’s Brochure or SmPC) of the medicinal products can be found in section.
  • Specify the mitigation measures described in the protocol to manage any new safety issues and if these new safety issues are adequately covered in the subject information leaflet.

The Cover letter and Modification description should be uploaded under the Forms section in the left side menu. If applicable, supportive documentation should be uploaded (e.g. publications supporting revision of inclusion or exclusion criteria) and Reason and Scope for the substantial modification should be ticked off in the drop down list. 

The first substantial modification after transition

For updates concerning Part I and Part II, see CTCG Best Practice Guide to sponsors updating the application dossier Part I after CTR transition_vs 2.0 and Annex III First SM Part II after transition respectively.

The labelling requirements from the old legislation will apply until a substantial amendment application for e.g. no labelling of IMP has been approved, see applicable IMP labelling requirements in SOP Investigational Medicinal Product (IMP) at Trial Start, section on Labelling.

If the trial fulfills the criteria for a low-intervention trial, an SM application must be submitted  and approved before reduction in traceability of IMP and reduced monitoring can be implemented. The characteristics of low-intervention trials are described in SOP Application Process, Approvals.

Download

• Modification description - Template
• Cover letter SM - Template