4. Regulatory Authority (RA)/Competent Authority (CA)

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. 

Under the EU CTR, the initial application for a clinical trial is divided into two parts:

• Part I contains scientific and medicinal product documentation (this part is reviewed by the Competent Authorities of the Member States taking part in the application, and in some cases by some of the National Ethics Committees).
• Part II contains the national and patient-level documentation. It is reviewed by the ethics committees of the Member States taking part in the application. Details of Part II documents relevant to Spain are listed in Section 3.1.

See below the list of applicable documents for Part I, as described within the AEMPS- CTIS Sponsor Guidance document:

1. EU Application form; data entered directly in CTIS: According to transparency rules, a translation into Spanish of the fields to be published in the REEC (Spanish Clinical Studies Registry) shall be included (title, investigated disease, objectives, endpoints, and inclusion-exclusion criteria).
2. Cover letter
3. Protocol
4. Patient-facing documents linked to the clinical trial endpoints shall be provided together with the protocol in part I of the clinical trial application.
5. Protocol synopsis: it must contain all the information described in question 5.8 of the Questions and Answers document - EU Regulation 536/2014, published in the Chapter V of the EudraLex Volume 10- Clinical trials guidelines. Spanish version of the protocol is required.
6. The two-page requirement is only orientative. Sponsors should consider making the synopsis understandable to the layperson. If a layperson version is created by the sponsor, only this version is to be submitted.
7. Charter of the Data Safety Monitoring Committee (if applicable)
8. Investigator’s Brochure/Summary of the Product Characteristics
9. Documentation relating to compliance with Good Manufacturing Practice (GMP) for the IMP
10. IMPD quality, safety, and efficacy/Simplified IMPD with reference to the valid SmPC
11. Auxiliary medicinal product dossier
12. Scientific advice and pediatric investigation plan (PIP) if available
13. Content of the labeling of the IMP in Spanish

As per Art. 21.2 of Spanish RD 1090/2015, the documents to be submitted along with the application are the same as listed in Annex I of the EU CTR. 

4.2 Time required for RA/CA review and approval process and turnaround time if any query is raised during the review process. 

The local Spanish legislation relies on the timelines mentioned in the EU CTR 536/2014. The timelines set out in the table below, are 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:

• 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.

CTIS evaluation timelines have also been published by the EMA.

4.3 Does the regulation support electronic submission?

Yes, all documents are to be submitted electronically through CTIS.

4.4 Does the regulation require the applicant to be Principal Investigator (PI)/Chief Investigator (CI)?

No, submission of clinical trials as per the EU CTR 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 CTIS portal. The CTIS Handbook is helpful in this regard.

Relevant provisions of the Spanish RD 1090/2015 are provided below:

“Art. 21. Submission of applications and receipt of notifications.

1. Sponsors will submit their applications and communications and will receive notifications through the portal mentioned in Article 80 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014 ("the portal of the EU"), addressed to the Spanish Agency for Medicines and Medical Devices and to the CEIm that has accepted the evaluation.

2. The documentation that must accompany the application for authorization and opinion of the clinical trial is included in Annex I of Regulation (EU) No. 536/2014 of the European Parliament and of the Council, of April 16, 2014, in the current European guidelines and, where appropriate, in the instructions for conducting clinical trials in Spain that, in development of the aforementioned annex I, are published by the Spanish Agency for Medicines and Medical Devices.

Art. 22. Validation of the application.

1. The Spanish Agency for Medicines and Medical Devices will assess the acceptance or not of the character of "clinical trial" for the study and will verify that the application is complete with respect to the documents in part I to carry out the evaluation referred to in the Article 6 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014.

2. The CEIm will verify that the application is complete with respect to the documents in part II to carry out the evaluation referred to in Article 7 of the aforementioned Regulation (EU) No. 536/2014 of the European Parliament and of the Council of 16 April 2014.

3. The validation will be carried out in such a way that the deadlines and the procedure provided for in Article 5 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014, are met.

Art. 23. Part I of the evaluation report.

1. The Spanish Agency for Medicines and Medical Devices will be in charge of notifying the sponsor of part I of the evaluation report, integrating those aspects that have been evaluated by the CEIm, so that the sponsor is notified within the deadlines and according to the procedure indicated in article 6 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014.

2. The CEIm's participation in the evaluation of Part I will be established in the collaboration memorandum referred to in Article 18, as well as the deadlines for transmitting its report to the Spanish Agency for Medicines and Medical Devices, in such a way that what is indicated in the previous section can be fulfilled.

3. In the case of an evaluation coordinated by a notifying Member State, the provisions of paragraph 2 of article 8 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014 will be taken into account. 

Article 24. Part II of the evaluation report.

The CEIm will be responsible for preparing part II of the assessment report in such a way that the deadlines and procedures set forth in Article 7 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16 are met. of 2014.

Article 25. Resolution of authorization.

1. The head of the Directorate of the Spanish Agency for Medicines and Medical Devices, within a period of five days as provided for in article 8 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council, of April 16, 2014, will issue a resolution authorizing the clinical trial, authorizing it with conditions or denying its authorization.

2. The resolution issued will put an end to the administrative process, so the interested party may file an optional appeal for reinstatement in accordance with the provisions of articles 116 and 117 of Law 30/1992, of November 26, on the Legal Regime of Public Administrations and the Common Administrative Procedure, or contentious-administrative, in accordance with Law 29/1998, of July 13, of the Contentious-administrative Jurisdiction.

3. The authorization of the clinical trial will be understood without prejudice to the application, when appropriate, of Law 9/2003, of April 25, which establishes the legal regime for the confined use, voluntary release, and commercialization of modified organisms genetically.”

These provisions are in alignment with the articles of EU CTR.

4.6 Does the RA/CA provide written acknowledgment of the submitted application? If not, describe how the application is tracked.

Yes, the Reporting Member State (RMS) will notify the sponsor as well as the other Member States concerned, through the CTIS portal, within six days from the submission of the application dossier. 

See Art 5.1, Clinical Trial Regulation (EU) 536/2014.

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.)

The fee payable for different procedures relating to Clinical Research can be found in Group V - Clinical Research under the List of Codes and Amounts of Fees, published by AEMPS. 

Article 33 of the Spanish RD 1090/2015 requires there to be a single payment for each Member State for the evaluation of a trial.

“Article 33. Fees.

1. In accordance with article 87 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council, of April 16, 2014, the payment of a single fee will be required for the evaluation of a clinical trial, regardless of the fact that various organizations are involved in the evaluation. This rate will be fixed in the current legislation in a transparent manner and on the basis of the principle of cost recovery. The sponsor must pay it to the Spanish Agency for Medicines and Medical Devices, which will be in charge of transferring the part corresponding to its evaluation to the CEIm."

Note that as indicated in Article 125.2 of the Spanish RD 1/2015, once the fee has been paid, the taxpayer must submit the application within a maximum period of one month from the date of the payment.

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?

Electronic payments can be made to AEMPS through its online Payment of Fees portal.

The AEMPS provides different options for the payment of fees, more information can be found on the AEMPS website under Payment of Fees.

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 CTIS portal. This is the only application that needs to be made, in terms of the EU CTR.

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 facility.

Below are some of the guidance documents made available by the EMA:

1. Getting started with CTIS – Sponsor Quickguide
2. CTIS Sponsor handbook
3. Reference Materials for Clinical Trial Sponsors

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. Please refer to sections 3.11 and 4.1 for more information.