4. Regulatory Authority (RA)/ Competent Authority (CA)
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4. Regulatory Authority (RA)/ Competent Authority (CA)
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4.1 Provide a list of documents needed to be submitted for RA/CA review and approval including the number of copies and/or translations as relevant.
The EU Regulation 536/2014 specifies that the documents to be evaluated are divided into two sections:
- Part 1 (including protocol and investigator information, benefit-risk assessment; see Article 6)
- Part 2 (including requirements for consent; recruitment; suitability of the trial site as well as persons involved in the conduct; data protection; insurance; and handling of biomaterials; see Article 7)
Those are submitted via the CTIS portal (the EU’s Clinical Trials Information System).
Additionally, the content of the file for a clinical trial application is defined in Annex 1 of the EU CTR 536/2014.
In Section 3.1 of this guidebook, we have defined the specific contents for Part II. In this section, we will indicate the contents for Part I. Additional information can also be found on the MPA page “Application documents checklist”:
PART I
Document | Requirement |
Cover letter | To enable the trial to be identified, the EU trial number, the protocol number, and the characteristics of the clinical trial shall be stated in the cover letter to the application. For information on additional information to be included in the cover letter, see Annex I, Section B to the CTR. |
EU CTIS Application Form | Correctly completed EU application form in CTIS |
Protocol | The trial protocol shall describe the purpose, design, methodology, statistical considerations, objective, and structure of the trial. Any questionnaires and self-assessment forms for subjects that are linked to the study endpoints are expected to be included as part of the protocol. Note that information directed at subjects must be in Swedish.
The protocol should be written in a searchable format, rather than in the form of scanned images. Signatures of the protocol are not needed for the application in CTIS but signed versions (of both investigator and sponsor) need to be available in the documentation at both the investigator and the sponsor according to ICH-GCP.
Annex I, Section D to the CTR lists what shall be included in a protocol. |
Protocol Synopsis | A synopsis (summary) of the protocol shall be included.
Note that it must be written in Swedish and should be understood by a lay person, and preferably not be longer than two A4 pages long.
More information on what this summary should contain can be found in Chapter V, Questions & Answers Document – Regulation (EU) No 536/2014. |
Investigator’s Brochure | The Investigator’s Brochure (IB) is a compilation of clinical and non-clinical data on the investigational medicinal product(s) relevant to the trial of these medicinal products in humans. The IB shall contain a clearly identifiable section called Reference Safety Information (RSI). If the investigational medicinal product is authorized and used in accordance with the authorization, its summary of product characteristics (SmPC) constitutes the IB. If the SmPC differs between the Member States included in the application, the sponsor should choose the SmPC that best guarantees patient safety. |
Documentation on investigational medicinal products, auxiliary medicinal products, and GMP | Annex I, Section F to the CTR specifies the GMP documentation to be attached to the application. Annex I, Sections G and H list what shall be included in the quality documentation for investigational medicinal products, (including placebos) and auxiliary medicinal products. |
IMPD / SmPC | An investigational medicinal product dossier (IMPD) or, if applicable, a simplified IMPD, or a SmPC shall be attached for each investigational medicinal product (including placebos) and auxiliary medicinal product. Note that the dossier shall be submitted in two parts:
Guidance on the content of the IMPD – Quality:
In order to facilitate the Swedish MPA's assessment, it is an advantage if, where applicable, it is made clear (for example in a list) what changes have been made in the IMPD compared with the previous version submitted to the authority. |
Scientific advice and pediatric investigation plan
| If scientific advice has been provided by EMA, in any Member State or in a third country in relation to the clinical trial, a copy of the scientific opinion of that agency shall be attached, if available.
If the trial is part of an agreed pediatric program, a copy of the national competent authority’s decision shall be attached together with the opinion of the Pediatric Committee. |
Labels | The labeling of investigational medicinal products and auxiliary medicinal products shall be in accordance with Chapter X, Articles 66 to 67 and Annex VI, Sections A to D of the CTR, and also in accordance with the Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use, Section 6.6 (Labeling).
For the labeling of radioactive medicinal products, see Article 68 of the CTR. According to the national regulations HSLF-FS 2021:109, the labeling of investigational medicinal products and auxiliary medicinal products shall be in Swedish. The investigational medicinal product may also be labeled in other languages. In certain exceptional cases, English labeling may be accepted after being justified in the application. Such an exception may, for example, apply to a hospital trial where the medicinal product is only handled in the clinic by a few people who are well acquainted with the trial. |
4.2 Time required for RA/CA review and approval process and turnaround time if any query is raised during the review process.
The timelines are set out in the table below, based on Art 5 (Application), Art 6 (Assessment report – aspects covered by Part I) & Art 7 (Assessment report – aspects covered by Part II), of the EU CTR 536/2014:
Validation | Part I Assessment | Part II Assessment | Decision | Total Time | Outcome |
Initial CTA | |||||
10 days (+10 / +5)
| 45 days (+12 / +19) RMS
| Same as Part I MSC | 5 days | 60 - 65 days (max. 106 days) | Authorized; Authorized subject to conditions; Rejected |
Additional MS | |||||
N/A | 10 days (+10 / +5) RMS | Same as Part I MSC | N/A | 52 days (max. 106 days) | Authorized; Authorized subject to conditions; Rejected |
Substantial Modification | |||||
6 days (+10 / +5)
| 38 days (+10 / +5) RMS
| Same as Part I MSC | 5 days (Pt I) N/A (Pt II)
| 44/49 days (Max. 90/95 days) | Authorized; Authorized subject to conditions; Rejected |
- In red: Time for sponsor to respond to questions (RFIs).
- In green: Time for RMS or MSC to assess and discuss responses.
- RMS: Reporting Member State
- MSC: Member State Concerned
If the response to the RFI is not submitted within the timeframe provided, the application will lapse.
4.3 Does the regulation support electronic submission?
Yes, all documents are to be submitted electronically through the EMA CTIS portal.
4.4 Does the regulation require the applicant to be a Principal Investigator (PI)/Chief Investigator (CI)?
No, submission of clinical trials, as per the EU CTR 536/2014, can be done by the Sponsor or authorized representative.
4.5 Please describe the process of RA/CA submission for clinical trial approval.
A Clinical Trial Application needs to be made through the EMA CTIS portal. The CTIS Sponsor Handbook is helpful in this regard.
4.6 Does the RA/CA provide written acknowledgment of the submitted application? If not, describe how the application is tracked.
Yes, within six days of submission of the application (Art 5.1, CTR 536/2014).
Tracking is via CTIS.
4.7 What is the relevant RA/CA fee in local currency/USD? Please provide as much information as possible (e.g. if the fee is different for notification/approval, initial submission, amendment, study with IMPD and study without IMPD, etc.)
According to the Ordinance (2010:1176) on fees for the state control of medicinal products (in Swedish Förordning om avgifter för den statliga kontrollen av läkemedel), applicants conducting clinical trials must pay an application fee. The fee contributes to financing the processing of the application and the Swedish Medical Products Agency’s supervision of the clinical trials.
Fees related to medicinal products for human use:
Application fee for clinical trials according to EU-Regulation 536/2014 | |
Sweden designated as a reporting Member State | 76 000 SEK* |
Sweden is concerned (not reporting) Member State (both for new application and when Sweden is later added) | 71 000 SEK* |
Sweden is the only concerned Member State (mono-national application) | 71 000 SEK* |
Application related to a significant modification in aspects covered by Part I of the assessment report (Chapter III of the Regulation) | 12 500 SEK** |
Application related to a significant modification in aspects covered by Part II of the assessment report (Chapter III of the Regulation) | 2 700 SEK** |
* Of which 16 000 SEK refers to the Swedish Ethical Review Authority’s processing
** Of which 2 000 SEK refers to the Swedish Ethical Review Authority’s processing
4.8 Does RA/CA accept checks or can payment be made electronically? Please provide details on (1) A/C number; (2) A/C Name; (3) Sort Code; (4) Swift Code; (5) Bank address, etc. Where can remittance advice notices be sent?
Yes, payment may be made electronically.
For a clinical trial application to become valid, a document with invoice details must be attached to the application/uploaded under “Proof of payment” in the Clinical Trials Information System (CITIS).
When an application is deemed valid, an invoice will be sent to the applicant. The invoice must be paid even if an application for a fee reduction has been submitted.
If a fee reduction is granted, a refund of all or part of the fee will be issued.
In case of resubmission, the application fee must be paid again.
Detailed information can be found on the MPA website - “Invoice documentation for clinical trial application.”
4.9 Is there any guidance tool available for making an electronic application? If yes, provide the link and/or step-by-step instructions.
The Clinical Trial application is made by the centralized EMA CTIS portal.
Sponsors wishing to use CTIS must have an EMA account. Users who do not have an EMA account can register through the EMA Account Management facility.
Organizations may need to go through additional registration steps based on the user management approach that was used for CTIS. The organization-centered approach enables user management by an administrator at the organization level, rather than at the level of an individual trial. This is intended for organizations that run various trials through CTIS. To make use of this organization-based approach, organizations must ensure that they are registered in the EMA Organization Management System (OMS) and must register a CTIS High-Level Administrator through the EMA Account Management webpage.
Below are some guidance and training modules made available by EMA:
- Getting started with CTIS – Sponsor Quickguide
- CTIS Sponsor handbook
- Reference Materials for Clinical Trial Sponsors
Additional information can be found on the MPA website.
4.10 Does RA/CA require any screenshots/mock screens for participant-facing materials?
Not under Part I of the application.
Participant-facing material is only submitted within Part II of the application unless participant-facing material is linked to the endpoints of the clinical trial, and those shall be provided together with the protocol in Part I of the clinical trial application. However, there is no indication as to how those documents should be provided.
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