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Documentation requirements for clinical trial applications

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All clinical trials of medicinal products involving humans that are to be conducted in Norway and/or other EU/EEA countries must be submitted through the European portal, the Clinical Trial Information System (CTIS)

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    Regulation (EU) No 536/2014 (CTR), Annex I, describes in detail the documentation that must be included in an application for a clinical trial. Please note that the documentation requirements may vary depending on the type of trial, the medicinal product, and other relevant factors. See also our advice and recommendations below.

    Cover letter

    The cover letter is an important part of the application and should include all key information about the clinical trial. For information on which details must be included in the cover letter, see CTR Annex I, Part B, Cover Letter.

    The document “Questions and Answers Document - Regulation (EU) 536/2014” also addresses questions relating to cover letters.

    Templates for cover letters are available on the CTCG website under the list “Key Documents”, in the section “Template cover letters and RFI Response”. We encourage all applicants to use these templates.

    Regarding Reference Safety Information (RSI): if the RSI is included in the Investigator’s Brochure (IB), the cover letter must specify the relevant section and chapter containing this information. If the Summary of Product Characteristics (SmPC) is used, it must be specified that the RSI is section 4.8 Undesirable effects.

    Invoice information must not be included in the cover letter. Instead, it should be uploaded under Proof of payment in the Form section of the application in CTIS.

    If the application is a resubmission of a previously withdrawn or lapsed application, both the new and the previous EU CT number must be stated in the cover letter. The cover letter must also describe the changes made in the new application compared to the previous one. Any unresolved questions raised by the authorities must be addressed in an attachment to the cover letter.

    Digital application form

    A digital application form must be completed manually in CTIS. Mandatory fields are marked with (*) and must be completed in order for the application to be technically possible to submit.

    Study protocol and protocol synopsis

    The study protocol must describe the objectives, design, methodology, statistical considerations, and how the clinical trial will be conducted.

    The protocol must be submitted in a searchable and copyable format, not as scanned images. Annex I, Section D of the Regulation describes the required contents of a study protocol. It is not necessary to submit a signed version of the protocol, but signed versions must be retained by both the investigator and the sponsor in accordance with ICH-GCP.

    A study summary (protocol synopsis) must also be included with the application. The synopsis must be in Norwegian and written in language understandable to laypersons. It should not exceed two A4 pages. Further information on the required contents of a protocol synopsis can be found in section 5.8 of the Questions and Answers Document - Regulation (EU) 536/2014.

    If materials intended for study participants are to be used, such as questionnaires, interview guides, or similar documents related to the study endpoints, these must be uploaded under “Part I” – “Protocol information” in CTIS. These study materials may be provided in either Norwegian or English.

    Scientific advice and Paediatric Investigation Plan (PIP)

    If scientific advice relating to the clinical trial has been obtained from Norway, the EMA, or another Member State, a copy of the summary of the authorities’ recommendations must be included with the application.

    If the clinical trial is part of a paediatric development programme, a copy of the Paediatric Committee Final Summary Report for the Paediatric Investigation Plan (PIP) must be included with the application.

    Documentation related to medicinal products / AxMPs / placebo

    Investigator’s Brochure (IB) and Summary of Product Characteristics (SmPC)

    The Investigator’s Brochure (IB) is a compilation of clinical and non-clinical data relating to the investigational medicinal product(s) used in a clinical trial. Annex I, Section E of the Regulation describes the required contents of an IB.

    If the investigational medicinal product is authorised and used in accordance with the marketing authorisation, it is sufficient to submit the Summary of Product Characteristics (SmPC).

    Quality documentation for investigational medicinal products / Good Manufacturing Practice (GMP)

    CTR Annex I, Section F specifies the GMP documentation that must be included with the application. Annex I, Sections G and H describe the required quality documentation for investigational medicinal products, including placebo and Auxiliary Medicinal Products (AxMPs).

    According to the guideline “Auxiliary Medicinal Products in Clinical Trials”, unmodified authorised AxMPs only need to be listed in the cover letter. They do not need to be registered under the “Product Section” in CTIS.

    Investigational Medicinal Product Dossier (IMPD)

    The Investigational Medicinal Product Dossier (IMPD) contains data on the quality, manufacture, and control of a medicinal product under development.

    The IMPD consists of two parts:

    1. IMPD Quality: contains information on the active medicinal product, placebo, and reference product (where applicable).
    2. IMPD Safety and Efficacy: contains a summary of data from all clinical and non-clinical studies, including an overall assessment of risks and benefits. For this section, reference may also be made to the IB – Investigator’s Brochure.

    If the investigational medicinal product (IMP) is authorised in the EU/EEA or has a marketing authorisation in an ICH country, a valid SmPC current at the time of application may be submitted. Table 1, Section G of Annex I to the CTR provides an overview of the data required for a simplified IMPD.

    If the IMP has marketing authorisation in several concerned Member States with different SmPCs, the sponsor must justify the choice of the most appropriate SmPC.

    Placebo

    For placebo products, the documentation requirements are limited to quality data. No additional documentation is required if the placebo has the same composition as the test medicinal product (except for the active substance), is manufactured by the same manufacturer, and is non-sterile.

    For further information on the required contents of an IMPD, see “Requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials”.

    Labelling

    The requirements for the labelling of medicinal products used in clinical trials (IMPs and AxMPs) are set out in CTR, Chapter X Labelling. A list of the information that must appear on the outer and inner packaging can be found in CTR Annex VI.

    No additional labelling is required for authorised medicinal products unless specific circumstances make it necessary to ensure the safety of trial participants. For example, additional labelling is required for blinded studies, or when an authorised medicinal product is used off-label in a vulnerable patient population where such treatment is not standard clinical practice.

    The labelling requirements under the CTR do not apply to radiopharmaceuticals used as diagnostic IMPs or diagnostic AxMPs.

    For clinical trials conducted in Norway, the label language must be Norwegian. English labelling is accepted for medicinal products handled exclusively by qualified healthcare professionals.

    Requirements for Part II of the application

    Part II contains documentation specific to each Member State in which the clinical trial will be conducted (informed consent forms, patient information, recruitment and data protection, compensation for trial participants, insurance, use of biological material, etc.).

    For an overview of the requirements for Part II of the application, please see the website of the Ethics Committee (REK KULMU).

    Tips and advice for the CTIS application process

    The application process in CTIS

    Application and application documentation / attachments

    1. Ensure that the application is complete before submission. It is important to familiarise yourself thoroughly with the applicable requirements.
    2. The information entered in the application form fields (structured data) must correspond to the submitted documentation. For example, the version numbers and dates in the documents must match the version numbers and dates entered in the structured data.
    3. Under the CTIS publication rules, certain documents will be published on the publicly accessible CTIS website. This includes, among others, the protocol and patient information documents. If these documents contain personal data or commercially confidential information, two versions must be uploaded - a complete version marked “not for publication”, and a redacted version marked “for publication”.
    4. Attachments must be named in accordance with the CTCG “Best practice guide naming of documents in CTIS”. See the link at the bottom of the page.
    5. All attachments must be submitted in a searchable and copyable format (preferably PDF files), not as scanned images.

    Questions to the applicant / Request for Information (RFI)

    1. Please note that email notifications are not sent when questions are issued by the authorities (Request For Information - RFI). Applicants must therefore log into CTIS regularly to check for updates.
    2. It is not technically possible to extend the deadline for responding to an RFI. If the deadline is missed, the application process will lapse, and the applicant must submit the application again. When resubmitting, a copy of the original application can be retrieved and resubmitted in CTIS, meaning the process does not need to start from the beginning.
    3. If application documents (for example the protocol) need to be updated in response to an RFI, a new version must be uploaded to the study dossier in CTIS. It is not sufficient to include the updated document only as an attachment to the RFI response. For further information, please see the “Handbook for Clinical Trial Sponsors”, section 3.3 “Respond to a Request for Information”.
    4. Updated documents must be uploaded both as a clean version and as a version with tracked changes.
    5. EMA has published recommendations addressing a number of common issues related to the assessment of Part I and Part II applications. See the link below.

    In the event of technical issues

    DMP does not have access to the sponsor section of CTIS and is therefore unable to assist with resolving technical issues in CTIS. If you experience technical difficulties when using CTIS, you must contact the EMA CTIS Service Desk.

    For non-commercial sponsors, the EMA CTIS Service Desk has established a dedicated HelpDesk. To indicate that you are a non-commercial sponsor, select “Non-commercial Sponsor” under User affiliation.

    Relevant links