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. 

As per Art 2(5) of the Ministry of Health Decree 27 Jan 2023:

“The documentation relating to Part II of the authorization application, referred to in Art 7 of the regulation (EU CTR 536/2014) can be presented according to the EU models collected in the Clinical Trial Guidelines “Eudralex Volume 10” or those defined by the National Coordination Center of the territorial Ethics Committees for clinical trials on medicinal products."

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):

3.2 Time required for EC/IRB 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:

• 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.

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

No. National and territorial ECs are established by Italian law, so do not require accreditation or approval by the AIFA. Please refer to Section 2.2 of this guidebook.

3.5 How frequently do EC/IRB meet?

The EC meetings must be held with a suitable frequency to respect the times established by current legislation for the evaluation of studies. Therefore, where necessary, extraordinary meetings will be called.

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

No, only EC approval is required prior to submission of CTA to RA/CA or AIFA.

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

The Clinical Trial application is submitted to the EMA CTIS portal; no separate application is required to be made to the Ethics Committee. 

EMA provides detailed training modules to help use the Clinical Trial Information System (CTIS).

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.)?

According to the Italian Ministerial Decree of 30 Jan 2023, a single fee is required to be paid to AIFA for the review of clinical trials. Please see Section 4.7 of this guidebook for more information.

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?

The application fee is required to be made to AIFA, the regulatory authority, and not the EC. Please refer to Section 4.7 for links to the fee schedule and electronic payment portal.

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, as described in Section 4 of this guidebook. This is the only application that needs to be made, in terms of the EU CTR 536/2014.

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 specifically addressed in national law or regulation. The EMA position applies, i.e. that patient materials such as informed consent forms and patient information leaflets are required to be submitted under the CTR, but that materials used post-consenting (patient cards, questionnaires, diaries) are not required to be submitted.

The Clinical Trial Regulation (EU) 536/2014 requires the electronic submission for Part II (National and Patient Level Documentation) of, among other things, “Patient materials: informed consent, patient information leaflet”. Therefore, screen mock-ups are likely to be expected.

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

Yes, the National Coordination Centre of Local Ethics Committees for clinical trials has published a guideline on the collection of informed consent to participate in clinical trials. Instructions and templates of ICF can be found within this guideline.

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

Yes. The Ministry of Health's Decree of 14 July 2009 specifies the requirements to be met by an insurance policy to be submitted to the EC with the clinical trial protocol and other required documents. The insurance policy must ensure the compensation for damages caused to trial subjects by the activities carried out in the course of the clinical trials, so as to cover the civil liability of the investigator and the sponsor, including those damages involuntarily caused as a result of an accidental event or because of negligence, imprudence or inexperience.

The maximum coverage should be no less than €1 million for each trial subject and no less than the prescribed thresholds for each clinical trial protocol, depending on the number of enrolled patients.

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

Information on safety reporting requirements is well described in the “Clinical Trials Regulation (EU) 536/2014 in practice, version 05_March 2024”, which can be found in the Eudralex Volume 10.

1. Reporting of adverse events and serious adverse events

The investigator shall record and document adverse events (AE) or laboratory abnormalities identified in the protocol as critical to the safety evaluation and report them to the sponsor in accordance with the reporting requirements and within the periods specified in the protocol. Any exception to the need to record and document all AEs should be included and justified in the protocol. The investigator shall report a serious AE (SAE) to the sponsor not later than within 24 hours of obtaining knowledge of the events, except for the SAE for which the protocol indicates that no immediate reporting is required. 

2. Reporting of suspected unexpected serious adverse reactions (SUSARs)

The sponsor of a CT shall report electronically to the EudraVigilance database all relevant information about the following suspected unexpected serious adverse reactions (SUSARs): - All SUSARs related to an IMP that occurred in any of the countries participating in the CT, even if the sponsor is aware of it only after the end of the CT. - All SUSARs related to the same active substance that occurred in a CT conducted in third countries by the same sponsor or by another sponsor within the same parent company or who develops the medicinal product jointly. The reporting period starts from the day the sponsor became aware of the reaction: - in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and not later than seven days. - in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not later than fifteen days.

3. Other unexpected events relevant for the CT subject’s safety

The sponsor shall notify the MSC through CTIS of all unexpected events that affect the benefitrisk balance of the CT that are not SUSARs. Reporting should be as soon as possible and no later than 15 days from the date the sponsor became aware of this event (e.g. the early end of another clinical trial with the same IMP due to safety reasons or results of a study showing genotoxicity for the IMP). 

4. Annual safety report

The sponsor shall submit annually via CTIS a report on the safety of the investigational medicinal product used in a CT for which it is the sponsor. The format for an annual safety report (ASR) is according to the ICH guideline E2F on development safety update report [24]. This obligation starts with the authorization of the first CT under CTR and ends with the end of the last CT conducted by the sponsor with this investigational medicinal product in any MS of the EU/EEA. In case of a CT involving the use of more than one investigational medicinal product, the sponsor may, if provided for in the protocol, submit a single safety report on all investigational medicinal products used in that CT. A simplified report is acceptable for low-intervention CTs and CTs with authorized IMPs.

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

No, annual safety reporting, along with other required notifications are submitted via the CTIS portal. Please refer to Section 2.16 of this guidebook.