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 any or all of the sponsor's trial-related duties and functions to a third-party vendor such as 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.

The coordinating investigator (CI) has the responsibility for ensuring that all protocol modifications are documented, and that substantial modifications are submitted through 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, or 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, will be submitted to the competent authorities and ethics committees.

If new circumstances or information arise regarding a clinical trial or investigational medicinal product (IMP) that could influence subject safety (benefit-risk balance), the CI will immediately take appropriate urgent safety measures to prevent injury to the subjects, 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 informed 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.

A modification to a trial can either be substantial or non-substantial. Non-substantial modifications (NSM) that are relevant for the supervision of the clinical trial by the authorities concerned should be entered into CTIS and are referred to as 81.9 NSM. The classification is described in the EU Q&A document, annex III.

In general terms, a substantial modification, 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 substantial modifications 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 of a principal investigator in a clinical trial site is considered a substantial modification.

To create a substantial modification, click “CREATE” in the upper right corner and select type of modification.

Please refer to Application Process, Approvals - SOP1.9.a, sections Application and Responses to RFIs, for guidance on how to complete the application and respond to RFIs.

The EMA template SM modification description and SM Cover letter 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 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 Investigational Medicinal Product (IMP) at Trial Start - SOP 1.8.a, section on "Labelling".

Application for categorisation of the trial as low-intervention, has also to be applied for as an SM after transition. The characteristics of low-intervention trials are described in Application Process, Approvals - SOP1.9.a.

• Description first SM after transition - Template