2. General Questions

2.1 Name of Regulatory Authority

Italian Medicines Agency/Agenzia Italiana del Farmaco (“AIFA”)

AIFA, the competent authority in Italy, is responsible for all aspects concerning the investigation (authorization and monitoring of clinical trials and supervision of observational studies and compassionate use programs), production and imports (e.g. granting of manufacturing or import authorizations), access to the market of medicinal products (including marketing authorizations, price negotiation and reimbursement procedure), as well as the post-marketing activities (e.g. pharmacovigilance, oversight of shortages and temporary unavailability and recalls).

Other stakeholders are as follows:

Ministry of Health (“MoH”)

MoH regulates narcotic drugs and psychotropic substances, medical devices, biocides, personal protective equipment, medical-surgical devices, food supplements, and other healthcare products. MoH is also responsible for ensuring the traceability of medicines throughout the distribution chain.

National Observatory on Clinical Trials/Instituto Superiore di Sanita (“OsSC”)

OsSC manages the authorization process of clinical trials conducted in Italy, provides consultative opinions on studies and amendments to Phase 1, and acts as an interface for transferring information to the European EudraCT database. Its functioning is managed by AIFA.

Regional or Local Health Authorities

Regional or local health authorities are responsible for granting licenses to warehouse keepers, wholesale distributors, pharmacies, and other shops where non-prescription medicines may be sold.

2.2 Name of Ethics Committee

National Coordination Centre of Local Ethics Committees

The National Coordination Centre of Local Ethics Committees coordinates, directs, and monitors the evaluation activities of the ethical aspects relating to clinical trials on medicinal products for human use and medical devices delegated to the local ethics committees.

The Italian decree of 11 January 2018 n. 3 provides for a reorganization of national and territorial ethics committees in order to comply with the requirements of the EU CTR. It provides for the establishment of 40 territorial ethics committees. 

The law of 11 January 2018 n. 3 also provides for the establishment, by ministerial decree, of three ethics committees of national significance, one of which is reserved for pediatric trials. 

On 7 February 2023, the four Ministerial Decrees provided for in Article 2 of Law No. 3 of 11 January 2018 (see section 1) on clinical trials on medical devices and medicinal products for human use were published in the Official Gazette.

On 28 February 2023, the Ministry issued a Circular providing guidance on how to apply the decrees and the implications of the new regulations.

In particular, the effects of the provisions introduced by the Decree of the Minister of Health of 30 January 2023, on the definition of the criteria for the composition and functioning of territorial ethics committees, and by the Decree of the Minister of Health of 26 January 2023, on the identification of 40 territorial ethics committees, must be considered.

On 23 March 2022, the “National Ethics Committee for trials conducted by public research organizations and other public organizations of a national nature” (“National Ethics Committee”) was established within the National Institute of Health (NIH) in accordance with the provisions of the decree of the Ministry of Health dated 1 February 2022. The National Ethics Committee was established on 23 March 2022 at the Italian NIH to replace the Ethics Committee of the NIH, which had been in office until that date.

The National Ethics Committee, which replaces the Ethics Committee of the NIH, is responsible for clinical trials and performs the functions of the territorial ethics committees as well as those relating to research bodies and public bodies of a national nature.

The establishment of the National Ethics Committee is part of the reform of the organization of ethics committees and the regulatory framework for clinical trials, also for the purposes of adapting to the provisions of EU CTR, which applies from 31 January 2022.

The Minister of Health’s decree of 1 February 2022 created a national coordinating center of territorial ethics committees for clinical trials of medicines for human use and medical devices, establishing the following:

1. National Ethics Committee for Clinical Trials of Public Research Bodies (EPR) and Other National Public Institutions, at the Italian National Institute of Health (Istituto Superiore di Sanità);
2. National Ethics Committee for Clinical Trials in the Pediatric Field, at the Italian Medicines Agency;
3. National Ethics Committee for the Trials of Advanced Therapies Medicinal Products (ATMPs), at the Italian Medicines Agency.

A list of operative Ethics Committees can be found on the AIFA website.

2.3 Clinical Trial Application Language

Italian or English. 

The application for authorization of a clinical trial to be submitted in accordance with Article 5(1) of the CTR 536/2014 shall be submitted via the Clinical Trial Information System (CTIS) in Italian or English.

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

Yes. Regulatory approval is required from AIFA, the National Coordination Centre of Local Ethics Committee.

2.5 Can regulatory authority and EC submission be done in parallel?

Yes. A single application submission for Part I (intended for AIFA review) and Part II (intended for EC review) can be submitted in parallel through the EMA CTIS portal.

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

Yes, the EU CT Regulation applies.

Art 61, Clinical Trial Regulation (EU) 536/2014:

“Authorization of manufacturing and import

1. The manufacturing and import of investigational medicinal products in the Union shall be subject to the holding of an authorization.

2. In order to obtain the authorization referred to in paragraph 1, the applicant shall meet the following requirements:

(a) it shall have at its disposal, for manufacture or import, suitable and sufficient premises, technical equipment and control facilities complying with the requirements set out in this Regulation;

(b) it shall have permanently and continuously at its disposal the services of at least one qualified person who fulfils the conditions of qualification set out in Article 49(2) and (3) of Directive 2001/83/EC (‘qualified person’)….”

2.7 Biological Specimen Export Requirements

Yes, the requirements and related regulations are described below.

Italy has implemented the European Dual-Use Export Control Annex, which defines dual-use items as goods and technologies that may be used for both civilian and military purposes and includes material that may be used for chemical or biological warfare. Export licensing responsibility for dual-use items in Italy is controlled by the Ministry of Foreign Affairs and International Cooperation.

EU Dual-Use Regulation 428/2009 was superseded by EU Regulation 2021/821, effective from 1 July 2022. 

As of 1 July 2022, an e-licensing system is to be used for applications for authorization of export of dual-use items. An EU Login profile is required to be created by an applicant via the E-Licensing portal; additional guidance on the eLicensing Dual Use is also available.

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?

Yes; studies of GMOs are permitted subject to the applicable rules.

The applications to seek authorization under clinical trial and GMO frameworks have to be submitted to the Italian Medicines Agency (AIFA) and the Ministry of Health (Competent Authority for the contained use).

In addition, if the assessment of a genetically modified microorganism (GMM) contained use shows that the medicinal product contains a GMO that can replicate, transmit, and disseminate into the environment, authorization under Part B of Directive 2001/18 should also be obtained from the Ministry for Environment and Energy Security (Competent Authority for the deliberate release). See here the authorization procedure.

Each of the above-referred applications can be submitted in parallel (i.e. the applicant can decide the timing of the submission). However, the authorizations issued by the Italian Medicines Agency, the Ministry of Health, and, where applicable, the Ministry of Environment have to be issued prior to the beginning of the clinical trial.

2.9 Is in-country sponsor presence/representation required?

Not specifically in Italy, but the Sponsor must be present or represented in an EU or EEA member state.

See Art 74, Clinical Trial Regulation (EU) 536/2014:  

“1. Where the sponsor of a clinical trial is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication to that legal representative shall be deemed to be a communication to the sponsor.

2. Member States may choose not to apply paragraph 1 as regards clinical trials to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.

3. As regards clinical trials to be conducted in more than one Member State, all those Member States may choose not to apply paragraph 1 provided that they ensure that the sponsor establishes at least a contact person in the Union in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.”

However, Clinical Research Organizations (CROs) wishing to conduct activities in Italy must have legal representation in one of the Member States of the European Union, self-register in the National Observatory on Clinical Trials of Medicines (OSSC), and comply with MoH Decree 15 Nov 2011 “Definition of minimum requirements for contract research organizations (CROs) in the field of clinical trials of medicines”, which sets forth the minimum requirements for CROs conducting clinical trials with investigational medicinal products in Italy. Note that MD 15 Nov 2011 does not apply to CROs conducting observational studies or clinical investigations with medical devices.

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country? 

Yes, a local investigator is required.

See Art 49, Clinical Trial Regulation (EU) 536/2014: 

“The investigator shall be a medical doctor as defined in national law, or a person following a profession which is recognized in the Member State concerned as qualifying for an investigator because of the necessary scientific knowledge and experience in patient care. Other individuals involved in conducting a clinical trial shall be suitably qualified by education, training and experience to perform their tasks”.

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator? 

No, under the EU Clinical Trial Regulation 536/2014, there is no role for a Chief or Coordinating Investigator, only for a Principal Investigator and Investigator.

Article 73, EU CTR 536/2014, indicates:

“A principal investigator shall ensure compliance of a clinical trial at a clinical trial site with the requirements of this Regulation. The principal investigator shall assign tasks among the members of the team of investigators in a way which is not compromising the safety of subjects and the reliability and robustness of the data generated in the clinical trial at that clinical trial site”.

A principal investigator is defined in Art 2 (2) (16) of the CTR 536/2014 as “an investigator who is the responsible leader of a team of investigators who conduct a clinical trial at a clinical trial site”, whilst an investigator is defined as “an individual responsible for the conduct of a clinical trial at a clinical trial site”.

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled? 

Yes, a written contract is required between the sponsor and the CRO, delegating authority. The contract does not need to be notarized and/or apostilled, so far as we are aware, at an EMA level, now that applications are made electronically.

Article 71, EU CTR 536/2014, provides clarification on the sponsor's role:

“Sponsor

A clinical trial may have one or several sponsors.

Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution, or an organization. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial. The investigator and the sponsor may be the same person.”

2.13 Is there a requirement to register clinical trials on a local registry or database?

Yes. From the 31^st of Jan 2023, all initial clinical trial applications in the EU/EEA must be submitted through the Clinical Trials Information System (CTIS). The status and results of all trials submitted under the CTIS will be available to the public.

EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trials Regulations 536/2014 are publicly accessible through CTIS. 

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

The clinical trial master file (TMF) must be retained for 25 years after the end of the clinical trial, whilst retention of medical files of clinical trial subjects is required to comply with the requirements of GDPR.

25+ years, with medical files for the subjects to be retained in accordance with national law. The format is unspecified, the requirements being that it be complete and legible – see Art 58, Clinical Trial Regulation (EU) 536/2014: 

“Archiving of the clinical trial master file

Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national law.

The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities.

Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article.

The sponsor shall appoint individuals within its organization to be responsible for archives. Access to archives shall be restricted to those individuals.

The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph.

Any alteration to the content of the clinical trial master file shall be traceable.”

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

Yes, the local regulation does require periodic safety reporting. Relevant provisions on periodic safety reporting are also a part of the EU CTR.

Articles 41 & 42, Clinical Trial Regulation (EU) 536/2014, relate to this.  

Art 41 CTR: “Reporting of adverse events and serious adverse events by the investigator to the sponsor

1. The investigator shall record and document adverse events 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.

2. The investigator shall record and document all adverse events, unless the protocol provides differently. The investigator shall report to the sponsor all serious adverse events occurring to subjects treated by him or her in the clinical trial, unless the protocol provides differently.

The investigator shall report serious adverse events to the sponsor without undue delay but not later than within 24 hours of obtaining knowledge of the events, unless, for certain serious adverse events, the protocol provides that no immediate reporting is required. Where relevant, the investigator shall send a follow-up report to the sponsor to allow the sponsor to assess whether the serious adverse event has an impact on the benefit-risk balance of the clinical trial...”

Art 42 CTR: “Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency

1. The sponsor of a clinical trial performed in at least one Member State shall report electronically and without delay to the database referred to in Article 40(1) all relevant information about the following suspected unexpected serious adverse reactions:

(a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred at a clinical trial site in the Union or in a third country;

(b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:

(i) by that sponsor, or

(ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product or information to a future potential marketing authorization holder on safety matters shall not be considered a joint development; and

(c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after the end of the clinical trial.

2. The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency shall take account of the seriousness of the reaction and shall be as follows:

(a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction;

(b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not later than 15 days after the sponsor became aware of the reaction;

(c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or non-life threatening but which turns out to be fatal or life-threatening, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening….”.

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

A safety report is required annually. Annual reports of clinical trials falling within the scope of the EU CTR 536/2014 shall be submitted to the EMA Clinical Trials Information System (CTIS).

Article 43, Clinical Trial Regulation (EU) 536/2014:

“1. Regarding investigational medicinal products other than placebo, the sponsor shall submit annually through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational medicinal product used in a clinical trial for which it is the sponsor.

2. In the case of a clinical trial 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 clinical trial.

3. The annual report referred to in paragraph 1 shall only contain aggregate and anonymized data.

4. The obligation referred to in paragraph 1 starts with the first authorization of a clinical trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor with the investigational medicinal product…”.

There are also other reporting/notification requirements, that will be required to be performed within the CTIS, those are:

2.17 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol? 

Yes, notification is required within seven days of becoming aware of the breach, in accordance with the provisions of the EU CTA.

Notification of a Serious Breach allows the sponsor to inform about a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial. These notifications must be made without undue delay but no later than 7 days from the date on which the sponsor became aware of the breach (article 52 of the CT Regulation). 

For more information, refer to the following EMA guidance on notification of serious breaches: 

1. Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol 
2. Appendix III b – Information to be submitted with a notification of a serious breach

2.18 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

Yes. The trial sponsor must submit to the ethics committee, together with the clinical trial protocol and other required documents, an insurance policy that meets the requirements laid down in the Ministry of Health's Decree of 14 July 2009. 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.