3. Ethics Committee (EC)/Institutional Review Board (IRB)

3.1 Provide a list of documents needed to be submitted for EC/IRB review and approval including the number of copies and/or translations as relevant. 

A list of all documents required to be submitted is provided by the EU CTR 536/2014 in Annex I:

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

1. 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).
2. Part II contains the national and patient-level documentation and is reviewed by the ethics committees of the Member States taking part in the application.

As per Article 21.2 of Spanish RD 1090/2015:

“2. The documentation that must accompany the application for authorization and an opinion on the clinical trial is set out in Annex I of Regulation (EU) No 536/2014 of the European Parliament and of the Council, of 16 April 2014, in current European guidelines and, if applicable, in the instructions for the conduct of clinical trials in Spain which, developing the aforementioned Annex I, are published by the AMPS”.

Additionally, the AEMPS has created a “CTIS Guidance for Sponsors” which can be found under the Guidance section within the “Regulation on Clinical Trials with Medicines for Human Use” webpage.

Requirements for Part II can be found on pages 18-20 of the “CTIS Guide for Sponsor” published on the AMPS website. The table can be found below (please use the arrow pointing to the right on your keyboard to view the entire row): 

3.2 Time required for EC/IRB 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. 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 536/2014:

• 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.

3.3 Does EC/IRB have any fast-track or expedited review process?

No; there is no fast track or expedited review process.

A shorter review timeline is prescribed only for observational studies with drugs that are not within the ambit of EU CTR or RD 1090; these are covered separately under Royal Decree of 957/2020 of November 03, 2020, which regulates observational studies with medicines for human use (“RD 957/2020”). Article 13.1 requires the CEIm to complete the evaluation within a period of 30 days. 

3.4 Does EC/IRB need to be registered and/or accredited/approved by RA/CA?

Yes, each Ethics Committee needs to be approved by the Spanish competent authority (AEMPS).

Article 13, RD 1090/2015, requires that each CEIm be accredited as per (i) requirements established for CEI accreditation in Law 14/2007 of July 03, on biomedical research and (ii) specific accreditation requirements mentioned in the RD 1090/2015. 

In addition, the AEMPS has also published a document titled “Common Specific Criteria for Accreditation, Inspection And Renewal Of The Accreditation Of The CEIm” on October 20, 2022, which lists the specific criteria for a CEIm to be accredited.

3.5 How frequently do EC/IRB meet?

The frequency of meetings differs from one CEIm to another as per their respective SOPs. The standardized work procedures established by each CEIm in Spain may contain such provisions. One must refer to the respective SOPs for each CEIm to understand their specific timelines and other procedural aspects of conducting meetings.

3.6 Is any additional approval required apart from the EC/IRB (e.g. scientific committee, subject matter expert committee, etc.)?

No, at a member state level, only the Ethics Committee and AEMPS need to review and approve a CTA for clinical studies conducted in Spain.

However, Article 16.4, RD 1090/2015 requires an Ethics Committee to seek advice from an expert when it does not have the necessary knowledge and experience.

Art.16.

“4. When the CEIm does not have the necessary knowledge and experience to evaluate a certain clinical study, it will seek the advice of at least one expert person not belonging to the committee, who will respect the principle of confidentiality. This advice will be considered specifically when:

a) The committee evaluates clinical research protocols with surgical procedures, diagnostic techniques, medical devices, or advanced therapies. In this case, they will have the advice of at least one person who is an expert in the procedure or technology to be evaluated.

b) The committee evaluates clinical trials that refer to subjects with special vulnerability. In this case, they will have the advice of at least one person with experience in the treatment of the population included in the trial and, where appropriate, in the treatment of the disease.”

3.7 Please describe the process of the EC/IRB submission for clinical trial approval.

The Clinical Trial application is made through the centralized CTIS; no separate application is required to be made to the Ethics Committee. Please refer to Section 4.5 of this guidebook for further details.

However, As per the AEMPS Instruction Document, it is recommended that the sponsor obtain the prior confirmation regarding availability from the Ethics Committee it chooses for evaluation of its CTA, especially where Spain is proposed to be the Reporting Member State. The sponsor can select the CEIm upon mutual agreement with such Committee in advance. 

It is advisable to consult the AEMPS webpage where the most up-to-date list of the CEIMs can be found. 

3.8 What is the relevant EC/IRB fee in local currency/USD? (e.g., is the fee different for notification/approval, initial submission, amendment, study with IMPD and study without IMPD, investigator site addition, etc.)?

There is a fee to be paid directly to the AEMPS for the review of clinical trials/investigations.

Subject to Article 33.1 of the RD 1090/2015 and Article 87 of EU CTR, which mandates a single payment for evaluation of the clinical trial application, per Member State. 

“Art.33.1. 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, with 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.”

For the payment of fees to the AEMPS, it is mandatory to access the “ telematic payment portal”, but there are two payment methods: by direct debit (bank transfer) or payment by credit or debit card (telematic payment).

3.9 Does EC/IRB 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?

As indicated in section 3.8 above, there is only one payment involved and this is to the AEMPS. At the time of the payment via the AEMPS portal, the choice of CEIm has to be indicated.

3.10 Is there any guidance tool available for making electronic applications? 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 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

3.11 Does EC/IRB require any mock screens/screenshots of participant-facing material on the app? If yes, do these need to be submitted in the local language?

From the research conducted, this issue is not addressed in such explicit terms, but can be assumed so given the existing provisions in the EU CTR.  

The EU CTR requires the applicant to submit “copies of all advertising material, including printed material audio and video recordings’ as well as “all information given to the subjects…’. This may mean to include the information given to subjects as-is, so mock-ups may be expected. 

Further, please see the answer (Paragraphs 77-81) to Q1.24 in the Q&A Document of EudraLex Volume 10, Chapter V, which talks about submitting patient-facing documents.

Patient-facing documents will be required to be submitted in Spanish.

3.12 Does the EC/IRB have any template or specific element requirements on ICF and/or other participant-facing materials?

The AEMPS Instruction Document provides a guideline for the correct preparation of a patient information sheet and informed consent form. Please see Annex VIIIA of the said AEMPS Instruction Document.

Note: We recommend that, in order to use the most up-to-date version, templates should be obtained directly from the AEMPS website as the Agency updates templates regularly.

3.13 Is there any guidance tool on participant compensation including clinical study-related injury per local requirements?

The template document for the Compensation of Trial Participants acts as guidance on the kind of compensation that can be offered. The AEMPS accepts the template provided within Chapter I- Application and Application documents within the EudraLex Volume 10 “Compensation for Trial Participants-Template”.

Legal provisions around the sponsor’s responsibility, as contained in Articles 9-10 of the Spanish RD 1090/2015, are already covered in Section 2.21 of this guidebook. 

3.14 Are there any specific local safety reporting requirements for clinical studies?

Yes, the investigator as well as the sponsor have safety reporting obligations.

Article 49 of the Spanish RD 1090/2015 requires the investigator to report any adverse events or abnormal laboratory results to the Sponsor. 

Article 50 of the Spanish RD 1090/2015 requires the sponsor to report any adverse events to the AEMPS. Further, the sponsor must report any information that affects the benefit/ risk ratio of the product in a trial to the CEIm and the AEMPS.

Section 10.3 of the AEMPS Instruction Document provides clarification on the requirements for reporting SUSARs, see below:

“Suspected serious and unexpected adverse reactions must be reported to the AEMPS but not to the CEIm. In all cases, whether the adverse reaction has occurred in Spain or another country, the notification must be made only through Eudravigilance_CTM. 

The narrative of the cases may be done in English or Spanish, in this case preferably accompanied by a summary in English. It is not necessary to submit semi-annual reports regarding serious and unexpected adverse reactions.”

3.15 Does the EC/IRB require any periodic study reporting?

Yes. Applications and communications regarding a clinical trial made through the CTIS Portal must comply with what is indicated in the Q&A document in chapter V of volume 10 of Eudralex EudraLex - Volume 10 (europa.eu) and the CTIS Guidance. CTIS notification is unique for both the AEMPS and the CEIm.

For studies not submitted to the CTIS portal, Article 53 of Spanish RD 1090/2015 will apply, requiring the sponsor to submit an annual safety report to AEMPS and the CEIm. Additionally, an ‘ad hoc’ assessment report is to be submitted whenever there is a relevant safety problem.