7. Decentralized Clinical Trials

7.1 Do the country regulations allow Decentralized Clinical Trials (DCT) elements (e.g., eConsent, ePRO administration, remote investigator site, etc.)?

Yes.

7.2 Is there any specific regulation/guidance on the use of DCT elements within a clinical trial?

Yes, within the European Union, the EMA published a “Recommendation Paper on Decentralized Elements in Clinical Trials” in Dec 2022. Italian provisions on DCT can be found in the Appendix of the EMA DCT recommendation paper.

The Italian authorities have not published any additional or complementary opinion on decentralized clinical trials yet.

7.3 What is the overall acceptability of DCT elements by the Italian Regulatory Authorities and Ethics Committees?

Overall, DCT elements are accepted but it is important that sponsors take into consideration the recommendations provided by the EMA.

Additionally, requirements can also be discussed with AIFA for study-specific trials.

7.4 Has a fully virtual trial (DCT) been conducted in the country yet? If so, please provide an example including the registration number and any link to it, whether COVID/non-COVID trials.

Yes, at least one clinical trial has been approved with a fully decentralized arm and is currently recruiting in Italy. This study can be found on the CTIS portal with reference number 2022-500449-26-00 organized by Trials@Home.

7.5 Are there any non-regulatory DCT initiatives in the country, such as where the investigator sites and local CROs founded an alliance?

The Italian Association of CROs (AICRO) as part of the European CRO Federation (EUCROF).

In March 2022, the Italian National Health Institute (“ISS”) published a playbook that analyzes study results of DCTs and proposes how they may be conducted effectively (“ISS Playbook”). 

Also, in July 2022, a multistakeholder expert opinion on priorities for methodology, regulatory affairs, ethics, and training entitled ‘Implementing Decentralized Clinical Trials in Italy: Why and How?” was published.

7.6 Are there any general considerations when using DCT elements in a study?

Sponsors must make sure that the study design and the DCT elements are fit for purpose, taking into consideration the intended population and the safety profile of the study drug, and ensuring appropriate risk management is applied.

Sponsors must provide to the authorities clarity, risks and benefits of using DCT elements in a study, demonstrating how participant safety (data and physical) and well-being are guaranteed, how GCP standards will be upheld, and how compliance with data privacy requirements (GDPR) and the Italian Data Protection Code (DPC) (Legislative Decree no.101 of 10 Aug 2018) will be maintained. 

When considering a DCT/hybrid study, it must be ensured that the sponsor and investigator are able to keep oversight of trial participant safety and well-being.

Oversight: 

• Providing clear roles and responsibilities.
• Documenting which tasks are conducted: where, when, and by whom and how oversight is maintained.
• Clear communication plan between the different parties involved: sponsor, investigator, participants, and service providers.
• Trial participants informed on information flow, and how to make contact with acute safety concerns/events, device malfunctions, and other questions.
• Training of participants and study staff in the use of any electronic platforms or devices to be used within the study.

It is important to conduct a trial-specific risk-benefit assessment when proposing a decentralized clinical trial (DCT). This assessment evaluates whether the proposed elements are suitable for the participant populations involved in the trial. Regulators typically expect this assessment to ensure participant’s safety and data integrity.

It is advisable for sponsors wishing to use decentralized elements in a clinical trial to discuss prior with the Italian Regulatory Authority (AIFA).

7.7 Considerations/Requirements for the Use of eConsent/Remote Consent

eConsent and remote consent are permitted in Italy.

AIFA’s response included under the “National provisions” appendix within the EMA “Recommendation paper on Decentralized Elements in clinical trials” - on question 11: Is a physical face-to-face meeting between the trial participant and the PI or a member of the research team always mandatory during the consent procedure (even if the rest is conducted remotely)?

AIFA’s Response: “CTR art.29 does not foresee face-to-face interview, no additional national provision exists on this aspect.”

The EMA Recommendation Paper on Decentralized Elements in Clinical Trials states that:

“An important aspect of a clinical trial is that the potential trial participants give their voluntarily informed consent to participate. To give consent, the potential participant needs adequate information. Informed consent is not only of ethical and legal importance: good communication between the investigator and the trial participant is beneficial for mutual trust and may promote trial compliance. Therefore, when considering the appropriateness of conducting the informed consent process in a remote manner, to use digital information leaflets, and/or to use electronic methods for the signature of the informed consent form, several aspects have to be thoroughly assessed. These include the design of the clinical trial, the characteristics of the trial population, and the risks, burdens and potential benefit related to participating in the clinical trial. 

The entire procedure for obtaining informed consent, i.e. the selection, the evaluation of the eligibility, and the actual informed consent process, should be described step-by-step in the clinical trial application to ensure appropriate ethical review. The rationale for not having a physical examination as part of this procedure should be given in the protocol or other protocol-related document. The sponsor should also describe in the protocol the chosen method for obtaining informed consent. 

Regardless if only a part of or the whole informed consent process is conducted remotely, the process should still be carried out in compliance with the principles laid down in the CTR or the CTD, ICH E6, the GDPR and national legislation. 

The informed consent process should be documented in a manner that allows verification of the receipt of information by the trial participant, the discussion between the person qualified to obtain the consent and the trial participant, as well as giving of the consent.” 

7.8 Considerations/Requirements for the Use of eSignatures

eSignatures are permitted in Italy.

AIFA’s response included under the “National provisions” appendix within the EMA “Recommendation paper on Decentralized Elements in clinical trials” - on question 12: Is it possible to use electronic signatures instead of wet ink? If yes, please specify in the footnotes which eIDAS category is expected for the electronic signature.

AIFA’s Response: “PADES electronic signature on pdf files is surely accepted; other formats (e.g. CADES) to be confirmed.”

7.9 Considerations/Requirements for Electronic Patient Reported Outcome (ePRO)

This is not specifically addressed in the national legislation. However, the Italian CA and ECs accept the use of ePROs within clinical trials.

The EMA “Recommendation paper on decentralized elements in clinical trials” makes some remarks with regard to ePRO:

“The trial participant should be fully informed in advance on how the information transmitted via digital tools, for example electronic Patient Reported Outcomes (ePROs), will be acted upon. It should be made clear to the trial participant that the investigator may not review such data in real time, and that if the trial participant experiences any specific safety concern, they need to directly contact the investigator to report such an issue.”

ePROs considerations are also reflected within the EMA guidance on “Computerized Systems and electronic data in clinical trials.”

7.10 Considerations/Requirements for Home Health Care (HHC)- Home Nursing

Home nursing is permitted in Italy.

The response from the Italian authorities on trial participants' oversight can be found under the EMA’s Appendix within the “Recommendation Paper on Decentralized Elements in Clinical Trials.”

EMA's summary of these recommendations can be found below: 

• Investigator to ascertain suitability for trial procedures to be conducted at the participant’s home.
• Inclusion/exclusion criteria should include provisions related to adequacy of participant’s home.
• Participant should be informed during the consent process about planned trial procedures conducted at their home.
• Trial-related procedures at home should only be done if the procedures do not cause additional risk to trial participant or reliability of the data and the person performing the task is qualified and/or trained to perform the task. 
• The sponsor and/or investigator should ensure that appropriate guidance and training are provided to the delegated person(s) to conduct the tasks at home correctly. 
• The insurance or indemnity or a guarantee or a similar arrangement foreseen by CTR or the CTD should be in place to cover any damage resulting from trial-related procedures performed at home. 
• Investigator should monitor compliance of the trial participant considering the lack of/decrease in the number of face-to-face visits/meetings between the trial participant and the investigator and/or delegated staff. 
• Trial participants should be given the opportunity to visit the investigator in person if needed/preferred and they should be able to have a direct contact line if further support to perform a trial-related task/collect data is needed. 
• There should be procedures in place for reporting and management of adverse events noticed by the trial participant or by any delegated person during home visits.
• The sponsor should provide alternatives if a trial participant is unable or not willing to use her/his/their own private device (mobile phone, tablet, etc.) to capture trial data. 

Qualification on the HHC will also depend on the type of responsibilities allocated to the individual HHC.

7.11 Considerations/Requirements for HHC - Home Lab Collection

In Italy, it may be permitted to collect biological samples from study participants. However, the sponsor should take into consideration EMA’s “Recommendation paper on decentralized elements in clinical trials.” 

Collection of biological samples at home may be permitted, as long as the procedures involved do not cause any additional risk to trial participants or to the reliability of the data, and the person performing the task is qualified and/or trained to perform the task. If biological samples are collected at home, it should be considered whether persons taking the sample are qualified and allowed by their local legislation to take the sample. In addition, adequate handling and storage conditions for the samples throughout the entire process should be assured.

There may be additional requirements at the country level, such as IATA training for handling infections and biological material.

7.12 Considerations/Requirements for Direct-to-Patient Study Product Delivery

According to the response provided by the Italian authorities within the Appendix “National Provisions Overview” of the EMA Recommendation paper on decentralized elements in clinical trials, delivering or dispensing investigational medicinal products to participants is permitted under certain circumstances (please see below).

The EMA’s “Recommendation Paper on Decentralized Elements in Clinical Trials” also states that:

“Where it is intended for the IMP to be delivered and/or administered at the trial participant’s home, a risk assessment should be completed to determine if such an approach is appropriate. The risk assessment should at a minimum take into account the following aspects: the knowledge and uncertainty of the IMP and its safety profile, the route of administration, the trial population, whether an observation period is required, the need for emergency plans, the preparation of the final IMP for administration, its stability, the storage conditions, and the robustness of IMP delivery logistics (the risk of an inadvertently IMP delivery to a non-intended recipient). 

The CTR aims to harmonize the rules of the conduct of clinical trials in the member states while setting high standards of quality and safety of IMPs to ensure the protection of public health. Therefore, the import of IMPs into the EU requires an authorization (CTR article 61), and the applicable principles of GDP should be considered in the logistics of IMPs. Shipping and the contractual agreements regarding IMP shipment between sponsor and investigator site or pharmacy are covered by the ‘Guideline on the responsibilities of the sponsor with regard to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing Practice’. IMP delivery to the trial participant is not, however, within the scope of that guideline. 

In this section, considerations are given concerning the delivery of the IMP and the administration at the trial participant’s home. 

Considerations on IMP delivery direct to trial participants 

• If the IMP is not dispensed to the trial participant by the investigator or delegated healthcare professional at the site, it is recommended that the vendors responsible for delivery to the participant are authorized to distribute or dispense medicinal products as much as possible. Any non-authorized vendor used in the logistics should be qualified and supervised by the authorization holder, in accordance with the principles of GDP. There must be a written contract which clearly establishes the duties of each party. It is recommended that the number of separate transportation steps are minimized. 
• The investigator remains responsible for the decision of treatment which should be documented (for example prescription or Interactive Response Technology system) prior to any delivery of IMP to the trial participant’s home. Delivery to the participant’s home could mean another suitable address the participant prefers to receive the IMP at, provided that: 
• regulatory requirements are complied with;
• risks of exposure to conditions that could impact quality and integrity of the product are minimized;
• the applicable principles of the guidelines on GDP of medicinal products for human use are taken into consideration.

When the given address is abroad, it should be verified whether the national legislation of that country allows the IMP to be delivered there (see appendix on national provisions). The given address should also be the place where the IMP is stored and administered, to avoid additional transport by the trial participants themselves. 

There are several options for delivery of the IMP to the trial participant’s home, depending on what is permitted by national requirements. This can include delivery from the pharmacy of the investigator site, from a delegated pharmacy, or from a depot. The sponsor has the overall responsibility for the process and the contracts or agreements, which should reflect the principal investigator’s responsibilities pursuant to ICH E6. Please refer to the appendix for the acceptable options in the member states regarding the delivery of the IMP to the trial participant’s home. The arrangements for delivery of the IMP to the trial participant should be described in the clinical trial protocol or the Investigational Medicinal Product Dossier. 

The sponsor should ensure that the personal data of the trial participants required for the delivery of the IMP is used in accordance with the GDPR on a need-to-know basis. For example, it should be ensured that personal data is solely accessible to those involved in the delivery of the IMP and will not be stored for other purposes than the delivery of the IMP. Access to personal data should be restricted as soon as the final delivery is completed. Information should be made available only for the purpose of monitoring, auditing, inspections, and to trial participants for the exercise of their GDPR rights. 

• Trial participants should be made aware during the informed consent process that their contact details will be used for delivery purposes if the IMP is to be delivered to the trial participant’s home. Details regarding the use of contact information should be outlined in the participant information. 
• When delivering the IMP, it should only be handed over to the trial participant (or a representative, if applicable), or the present healthcare professional involved in the clinical trial. Sponsor procedures should be in place covering delivery and receipt of the IMP. With regard to receipt of IMP, the procedure should detail the steps and responsibilities in relation to confirmation of IMP identity (e.g. batch number) to ensure that what has been dispatched has actually been delivered. In some cases, the trial participant (or a representative) may not be available to accept and sign the receipt of the IMP. In this case, the IMP should be brought back by the service provider to the original location (investigator’s site, (central) pharmacy, or depot). 
• As an alternative to delivering the IMP to the trial participant’s home, the IMP could be dispensed by local pharmacies (based on a prescription issued by the investigator), provided that the labeling requirements in the CTR or CTD are fulfilled, and if national requirements allow (see appendix). In particular, sponsors are reminded to consult Article 61(5) of CTR regarding labeling requirements. The local pharmacy should be aware that the prescription of the IMP is in the context of a clinical trial, and if necessary, be trained to dispense the IMP. 

Considerations on IMP storage and administration at the trial participant’s home 

• The sponsor and the investigator should consider during the planning stage of the clinical trial how the appropriate storage conditions of the IMP can be met, and whether the IMP is suitable for administration at home. The inclusion/exclusion criteria should include provisions related to the adequacy of the trial participant’s home for storage of the IMP, such as temperature control and restricted access where necessary. Sponsors may consider providing trial participants additional equipment necessary for IMP storage. This should be described in the protocol or other protocol-related document (e.g. pharmacy manual), including the documentation provided to participants. The investigator should give instructions to the trial participants on the use and storage of the IMP. The instructions should be realistic, and feasible and the additional burden for the trial participant should be part of the aforementioned risk assessment. 
• The investigator and the sponsor should consider whether administration at home can be done by the trial participants themselves or if a trained, experienced, and qualified healthcare professional is required for administration. In the case of complex administrations, special preparation or handling requirements, or when required by the safety profile of the IMP (e.g. unknown or potential serious adverse events in connection to the administration), healthcare professionals should always be involved. 
• Generally, if an IMP is required to be administered by a healthcare professional, shipping directly to the trial participant may not be appropriate. In the event it is required for IMP to be shipped directly to the trial participant separately, clear instructions for storage of the IMP prior to a healthcare professional visit should be given, as well as a clear explanation that the IMP is not to be administrated before the visit of the healthcare professional nor before the investigator’s decision. 
• If it is anticipated that the trial participants will prepare and administer the IMP as outlined in the protocol, they should be instructed in advance about these aspects. Where appropriate, there should be instructions provided regarding these steps as well as dosing, in addition to what is already present on the IMP label or package leaflet. These instructions should be adapted to the needs of the individual trial participants. The use of electronic step-by-step instructions which are easily and promptly accessible (such as QR code scanning), could be considered. Depending on the safety profile of the IMP, the investigator should contact the trial participants after the first delivery of the IMP to ensure proper handling of the IMP. The sponsor may consider providing additional equipment necessary for the safe administration, use and destruction of the IMP to the trial participants, in which case this should be described in the protocol or other protocol-related document (e.g. pharmacy manual), including the documentation provided to the participants. 
• The investigator should follow up, at regular intervals, with participants to ensure the IMP is taken appropriately and according to the IMP instructions. 
• Procedures should be in place for IMP accountability and treatment compliance of trial participants. These tasks fall under the investigator’s responsibility according to ICH E6. 
• Procedures should be in place for IMP return from the trial participant’s home, and destruction of the unused IMPs, in compliance with the protocol and local safety requirements. The procedure should also cover recalls during the conduct of the trial, and the steps taken to avoid that the IMP remains at the trial participant’s home beyond the envisaged treatment period.”

7.13 Considerations/Requirements for the Use of Telemedicine

While not specifically addressed in the national legislation applicable to clinical trials, telemedicine is permitted in Italy. In 2014, the Ministry of Health issued a national guideline on telemedicine - “The Guideline on Telemedicine” - (only in Italian) applicable to the health care settings.

Ethics Committees tend to enquire about the privacy settings of any platform used for telemedicine purposes and sometimes may request clarification if the software to be used is considered a medical device.

It is important to consider which are the study-specific assessments that are under the responsibility of the investigator (such as physical, neurological examinations, etc.) and if such assessments are related to the study endpoints. There may be instances where some assessments may be permitted to be conducted remotely, for example, where a qualified nurse is physically present with the study participant and the investigator is instructing or overseeing remotely via telemedicine. However, there may be occasions where those assessments can only be performed by a physician.

7.14 Considerations/Requirements for the Use of Wearables

Not specifically addressed in the existing national legislation, but support for their use may be found in the EMA's “Recommendation paper on decentralized elements in clinical trials” which makes some remarks with regards to wearables as part of handling data. 

References to Wearables as well as Bring Your Own Device (BYOD) can also be found within the EMA guidance on “Computerized Systems and electronic data in clinical trials”.

Additionally, AIFA’s Good Clinical Practice (GCP) Inspectorate released a statement in Jan 2024 titled “Use of electronic systems in clinical trials with medicines” noting the EMA guideline on “Computerized Systems and electronic data in clinical trials” and highlighting the GCP Inspectorate expectations that “responsibilities indicated in the EMA guideline does not only apply to sponsors but also to investigators and the investigational sites where the trial is conducted”.

7.15 Considerations/Requirements for Remote Monitoring

Remote monitoring can be permitted in Italy.      

The response from the Italian authorities on remote monitoring can be found under the EMA’s “Recommendation Paper on Decentralized Elements in Clinical Trials":

Additionally, the EMA’s recommendation paper indicates the following:

• “As detailed in ICH E6, the monitoring strategy should be based on the specifics of a clinical trial. These specifics may include, as applicable, decentralized processes and tools described in the previous sections. For example, if according to the trial protocol, safety and/or efficacy data are collected via ePRO or wearables, or if key processes (e.g. those related to primary endpoints) are performed outside the investigator site (e.g. at central reading facilities, central laboratories), the specific risks associated with these decentralized processes, tools, locations, and individuals involved should be taken into account in the monitoring strategy. 
• Monitoring procedures can be divided into centralized and site monitoring, and generally, a combination of them both is appropriate. Site monitoring is usually performed on-site. Depending on its purpose and suitability it may be performed off-site (remotely). 
• When establishing remote access for the purpose of monitoring, the principles of necessity and proportionality should always be adhered to. The monitoring strategy chosen should not unduly burden the site. 
• If remote access to source data and documents is foreseen, additional measures with respect to the confidentiality of data access and security of the systems should be in place. Further guidance on this is being drafted by the GCP IWG. See appendix with current national provision overview per MS whether remote access to medical records by the monitor or auditor is allowed.”

7.16 Considerations/Requirements for Digital Health Technologies (such as Platforms)

AIFA’s Good Clinical Practice (GCP) Inspectorate released a statement in Jan 2024 titled “Use of electronic systems in clinical trials with medicines” noting the EMA guideline on “Computerized systems and electronic data in clinical trials” and highlighting the GCP Inspectorate expectations that “responsibilities indicated in the EMA guideline does not only apply to sponsors but also to investigators and the investigational sites where the trial is conducted.”

It is therefore essential that the management of the healthcare facilities where clinical trials of medicines are conducted implement suitable measures so that the IT systems used in conducting the studies are in compliance with the regulations (ICH-GCP and EMA Guideline on computerized systems), as these requirements have now become essential to guarantee the protection of participants in trials and the integrity of the data to be presented to regulatory authorities.