CT SOP version no 1.13

• Main changes from version 1.12: Updated templates for cover letter and RFI response according to CTCG.
• Main changes from version 1.11: Updated transparency rules implemented in CTIS.
• Main changes from version 1.10: Link to Individual Participant Data (IPD) Sharing Statement inserted in table 4.1.1.3 Part I.
• Main changes from version 1.9: Link to Financial and other arrangements inserted, and link to EC webpage updated.
• Main changes from version 1.8: Updated template for financial arrangements.
• Main changes from version 1.7: Clarified duration of insurance (LAF).
• Main changes from version 1.6: Re-formatting and update of SOP.
• Main changes from version 1.5: Re-formatting and update of SOP.
• Main changes from version 1.4: Re-formatting and update of SOP.
• Main changes from version 1.3: updated with need for registration of trials in clinicaltrials.gov and detailing more for CTIS applications.
• Main changes from version 1.2: updated how to manage RFIs.
• Main changes from version 1.1: added guideline regarding recruitment strategy and other part II documents, added information about responses to RFIs.

Sponsor is responsible for ensuring that for all clinical drug trials approvals are obtained and that the trials are started in accordance with this SOP.

For multicentre trials, the sponsor has overall responsibility for ensuring written agreements with cooperating healthcare companies/other partners.

The sponsor’s responsibilities shall be described in the quality system of their institution. Tasks are delegated according to SOP Roles and Responsibilities in clinical trials implemented in the institution.

The sponsor is responsible for obtaining approval of a clinical drug trial by ethics committees and competent authorities and other concerned bodies.

The sponsor may transfer any or all 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 application for a clinical trial consists of Part I and Part II. Part I contains general study documents i.e. study protocol, study drug documentation, etc. Part II contains site-specific documents and patient-facing material (e.g. informed consent). In Norway, Part I will be assessed by both the Norwegian Medical Products Agency (NoMA/DMP) and Regional komité for medisinsk og helsefaglig forskningsetikk (REK), Part II by REK only.

Genetically modified organisms (GMO-IMPs):

For clinical trials with investigational medicinal products (IMPs) that contain or consist of genetically modified organisms (GMO-IMPs) for use in humans, application must be sent both in CTIS and to (see Clinical trials with GMOs in medicinal products - Norwegian Environment Agency).

Genetically modified micro-organisms (including viruses, viroids, animal, and plant cells in culture) may have to be carried out under containment until given to the patient, to limit contact of these organisms with the environment. Such activities include for example the process of genetic modification, the use, storage, transport,
destruction and disposal of GM microorganisms. NoMA (DMP) will involve the Health Directorate to assess whether approval for contained use is required. For details see Genterapi - Helsedirektoratet.

Application in the EEA

Low intervention studies

Low intervention studies have reduced requirements for traceability of IMP and monitoring. Sponsor must justify why the clinical trial is a low-intervention clinical trial in the application and argue for reduced documentation, see Risk proportionate approaches in clinical trials.

Studies can be regarded as low intervention studies if they fulfil the following conditions:

1. The IMPs are authorised;
   1. The IMPs are used in accordance with the terms of the marketing authorisation; or
   2. The use of the IMPs is evidence-based and supported by published scientific evidence on the safety and efficacy of those IMPs in any of the MSC, and
2. The additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any MSC.

Required documents

Annex I of REGULATION (EU) No 536/2014 lists the required documentation. The European commission has also prepared a Q&A document to complement the regulation. See here for International Trials - WI 1.2.d.

The submission documents are listed in the table below. In addition, the following documents are useful when preparing the submission:

• Investigational Medicinal Product (IMP) at Trial Start - SOP 1.8.a
• Language requirements for Part I documents can be found in the Q&A document, Annex II.
• The European Commission has provided guidance for submission of Part II documents, Overview part II requirements in a CT application per MS .

Special attention should be brought to the Informed consent and patient recruitment procedure (template)

• If hospital records (patient journals) are to be reviewed to identify potential trial subjects, this must be described in the recruitment procedures. The EC will then grant waiver from confidentiality. Without this such review of records cannot be done. Review should follow institutional procedures.
• The trial subject should not be in a dependent relation to the person who asks for the subject consent, e.g. have treated the subject for a while. Preferably the information should be given and the consent obtained by a study member who does not have a relation to the subject. In cases where this is not possible to avoid, e.g. small institutions, voluntary participation must be secured by other means, like substantial time to make the decision. This should be described in the application under Recruitment arrangements.
• Subjects that do not understand Norwegian should in general not be excluded from inclusion and should be given written and oral information in a language they master. For translations, check local procedure for possible translation agreement. REK does not need to approve the translations.

For guidance on special subject groups, see Veileder til helseforskningsloven.

Insurance:

In Norway, insurance should be purchased through Legemiddelansvarsforeningen (LAF). The coordinating investigator will ensure payment of the premium before the trial is initiated, and then every year for as long as the patients are undergoing trial specific procedures.

Naming and version control:

All documents must have an “ID” (e.g. acronym) and version number and date stated in the header or footer of the document. The document CTCG Best practice guide naming of documents issued by the Clinical Trial Coordination Group (CTCG) must be followed. During document upload, make sure to change the name of the document according
to the naming convention, and the date and version number must correspond with the date and version number of the actual document (not version date of template). Part I documents are coded B to J, and Part II documents K to R.

Redaction of personal information

The purpose of redacting documents and structured fields is to comply with GDPR.

Some trial documents and structured data will by default be published in EU Clinical Trials as soon as the application is approved. Special attention should be given to the inclusion of personal information, which should be redacted.

The personal information that should be published is the name and work-related contact information/affiliation of:

• The principal investigators.
• The Qualified person for GMP compliance documentation if applicable.
• The members of the DSMB if applicable.
• Sponsor staff such as contact point for union, scientific contact point and public contact point.
  All three functions may be held by the coordinating investigator, or not.
• The person issuing the Site suitability form.
• The person issuing the GDPR compliance statement.

No signatures should ever be published. Documents with wet ink signatures should be uploaded as “not for publication”. The first upload will per default be “for publication”, the second “not for publication”. Only the Qualified person for GMP compliance documentation and the person signing the site suitability form requires a
signature in the “not for publication” document.

All personal data included in metadata of a file should be removed, see Guide on CTIS common features.

All data from trial participants (e.g. patients) must be anonymised in “for publication” documents and in structured fields.

Signatures:

Signed versions of the documents must be archived in the Trial Master File/Investigator Site File (TMF/ISF).

Redacted or unsigned versions of the same documents should be uploaded in CTIS. Norwegian authorities do not require signed documents in CTIS, but authorities in other countries might. If signed documents are uploaded in CTIS, they should be uploaded as “not for publication” using the “add document” button.

Example:

The tables below refer to the different sections in the CTIS application portal and includes links to templates. If the templates are not used, a separate document should describe where the different items are covered.

Table 4.1.1.1 Forms

Table 4.1.1.2 Member state concerned (MSC)

Table 4.1.1.3 Part I

Table 4.1.1.4 Part II

Table 4.1.1.5 Evaluation

Table 4.1.1.6 Timetable

For submission of application for clinical trials in all EEA-countries, Regulation 536/2014 applies.

Roles

Coordinating Investigator (CI) must follow the institution’s procedure to get an EU CT number and applicable roles in Clinical Trial Information System (CTIS).

The Coordinating Investigator must request “CT admin” rights in CTIS to be able to assign roles to other qualified persons as appropriate for the trial. This is done while logged into CTIS Sponsor workspace and selecting “user administration” in the top menu, and then click on “Assign new role”.

To be assigned a role in CTIS for a specific clinical trial, each user must have an EMA account (ensure the correct organization name and ID for the sponsor is selected).

To request a role, a user will need to:

1. Get an EMA account. See EMA Account Manager.
2. Log on to CTIS, click https://euclinicaltrials.eu/home
   1. Select name at the upper right corner, then click “Personal profile” – “Update employer information” - choose the appropriate institution. Check the institution’s procedure to ensure the right organization name, number and address is chosen.
   2. Select name at the upper right corner, then click “My roles“, “Request role”, select your organization, scope= specific trial, enter EU CT number provided by CT Admin, select appropriate role. Several roles can be requested. The CT admin will then need to log on to CTIS and approve the roles (select “User
      administration” on the blue line → Search → select persons for whom roles should be approved → Approve → Confirm).

Alternatively, the CT admin can assign roles without the users requesting them. User IDs must first be shared with the CT admin.

Roles can be assigned for different parts of the application and further correspondence within CTIS: Part I, Part II, notifications, CT (both parts and notifications), Q-IMPD (the manufacturing part of the IMPD). Roles are also assigned at different levels; viewer, preparer (will also be able to view) and submitter (will also be able to view and prepare).

To be able to submit Annual Safety Reports (ASRs), a specific “ASR submitter” role must be applied for CTIS – M03 Registration of a new CTIS user – YouTube.

If the trial is to be conducted in several institutions, CI should require that the unregistered institutions get registered in the EMAs OMS database, see Clinical Trials Information System (CTIS) – Sponsor Handbook, section 3.2.1. The registration process can take up to 10 days.

As CTIS is a closed system that does not send information by emails, it might be useful to add a user whose task is to monitor the system for replies or requests for information (RFIs).

Application

See EMAs Training program, especially module 10.

The submission information is under four different tags: Form, MCSs, Part I and Part II.

Common rules:

• All fields with an asterisk should be filed in.
• The lock should be closed when editing (and open when submitting the application). Additional structured fields and request for documents may appear when the lock is closed.
• Documents should be uploaded as PDFs.
• Most documents will be made publicly available. It is specified in CTIS for each single section, see Revised CTIS transparency rules.
• Documents “not for publication” can be uploaded by clicking the “add document” button.
• To comply with GDPR, the use of personally identifiable information such as date of birth, signature, home address, children names, photographs etc. should be avoided. Use of CV for Investigators - Template is recommended.
• If the timelines are not met, the application will be cancelled in CTIS.
• Within 2 years from notification date, if no subjects have been included the authorisation shall expire in the MS.
• The CI should propose one of the member states concerned as reporting member state (RMS). For national trials the Norwegian Medicines Agency (NoMA/DMP) shall be the RMS. For a low-intervention clinical trial, where the IMP is not used in accordance with the terms of the marketing authorisation (MA) but the use is evidence-based, a member state where the use is evidence based, should be
  proposed as RMS.
• The authorities may answer earlier than stipulated in the flowchart. In Norway, the authorities have agreed not to send RFIs before Day 26. The authorities may also give the sponsor less than 12 days to respond. This is unusual unless the sponsor agrees to it.

Flowchart:

Responses to RFIs

For applications where RMS is Norway, the first RFI is expected to be issued at the earliest 26 days after validation of initial application.

Relevant videos:

• How to manage the workload in CTIS – RFI tab: where to find RFIs and sort them.
• How to respond to RFI considerations and submit an RFI response; how to respond, uploading supporting documents and submission.
• How to change a Clinical Trial Application as part of an RFI response.

See also FAQs.

How to respond to an RFI

• Revised documents should be submitted with track-changes and a clean version using the “update” button inside the trial dossier.
• The “Add document” button is used only for adding fully new documents, e.g. missing documents requested by the MS during validation. The System version will be 1.00. Please use document codes and titles as explained earlier.
• In the dossier;
  • Use the ”change application” functionality if changes are made to the dossier (IMPD, protocol, IB etc.).
  • On the top of left side of the RFI (just above “Supporting documentation”), click on "MSC: Norway Submission date" with the open lock symbol.
  • Then, on the right side of the RFI the button, “Change application” will appear. Changes should be done in the applicable section by using the “update” button. This will ensure correct versioning and publication in accordance with transparency rules.

How to make changes inside the dossier:

1. Click on the lock (upper right side of the window) to open the application.
2. Additional options will appear next to the document you want to update, delete or add.

A list of changes to the application dossier should be attached to the RFI response. It is recommended to use the EMA template RFI Response List of Changes to the Application.

The “Submit” option only appear at the end of the RFI when the “List of Changes” is uploaded and all locks are open (except the lock for the cover letter that should be closed).

When finished adding new/changed documents to the application, navigate back to the RFI response.

Similar documentation will be required in non-EEA countries as in EEA-countries. CI should seek information about application process.

Information should be gathered by using the Feasibility Questionnaire - Template. See also International Trials - WI 1.2.d.

The trial should also be published on the hospital's website once the trial is approved and ready for recruitment, according to local procedure.

CTIS is a registered data provider for the World Health Organization (WHO). Data from authorised trials published on the CTIS website is now included in the WHO’s International Clinical Trials Registry Platform (ICTRP). This applies to relevant clinical trial data, as required by WHO, published on CTIS since launch of the system on 31 January 2022. CI should verify that the trial is published on ICTRP before start of recruitment.

Approval from the competent authority and ethics committee is a pre-requisite for initiation of the trial. It is recommended that the Start-up Meeting Checklist - Template and the Start-up Meeting Agenda - Template are used to ensure that all requirements are complied with and all decisions are documented.

• Checklist Initiation of Clinical Trial - Sponsor - Template
• Start-up Meeting Agenda - Template
• Start-up Meeting Checklist - Template
• Compliance Norwegian Requirements on Data Protection - Template
• Financial and other arrangements - Template
• Protocol - Template
• Protocol Synopsis - Template
• Data Monitoring Committee Charter - Template
• CV for Investigators - Template
• Feasibility Questionnaire - Template