Decentralised clinical trials (DCTs): steps forward in the European and Italian regulatory frameworks

Elisa Stefanini

Portolano Cavallo, Milan

estefanini@portolano.it

Claudio Todisco

Portolano Cavallo, Milan

ctodisco@portolano.it

Decentralising trials to patients’ homes or local health care facilities is becoming increasingly common in medical research, boosted by the availability of new cutting-edge technological solutions that allow remote management and monitoring of patients, as well as the collection and processing of large amounts of data, including through artificial intelligence systems.

The sudden deployment of decentralised clinical trials (DCTs) during the Covid-19 pandemic, often on the basis of exceptional and temporary measures both at European level[1] and in individual Member States,[2] revealed the shortcomings of a general regulatory framework that was unable to guide the use of these new technologies. Emergency legislation had to address issues that were still under-regulated, such as the collection of remote consent, the shipment and management of investigational drugs at patients’ home, and the use of third-party service providers by sponsors and healthcare institutions.

This has formed the basis for the development of regulations and guidelines on DCTs beyond the emergency context, with the aim of creating a regulatory framework that is as uniform as possible across Europe and that can promote the decentralisation of research activities.

A clear example is the recommendation paper on DCTs issued in December 2022 as part of the Accelerating Clinical Trials in the EU (ACT EU) initiative launched in January 2022 to support the implementation of the new Clinical Trials Regulation and to strengthen the European ecosystem for the modernisation and development of trial activities.

As far as Italy is concerned, in August 2024, the Italian Medicine Agency adopted new guidelines on regulatory simplification and decentralisation for the conduct of drug trials in accordance with the Clinical Trials Regulation. This implemented several provisions of the European recommendation paper and provided Italian operators with the first regulatory document specifically dedicated to DCTs.[3]

ACT EU and its recommendations

On 14 December 2022, the European Commission, the Heads of Medicines Agencies (HMAs) and the European Medicines Agency (EMA) published a document entitled Recommendation paper on decentralised elements in clinical trials[4] (‘the Recommendations’) to provide Member States further and more detailed guidance on the implementation of procedures for conducting trials outside of traditional clinical trial centres.

The main guidance

The Recommendations focus on:

• the roles and responsibilities of all operators involved in a clinical trial;
• the process of acquiring informed consent remotely;
• delivery and administration of investigations drugs at patients’ homes; and
• data collection and management.

When trial activities are conducted outside a trial centre, potentially with the help of third-party service providers (such as home-care nurses or IT service providers), it is especially important that the roles and responsibilities of all those involved be clearly established before the start of the trial, including with regard to data collection and management. The activities of each should therefore be clearly described in the trial protocol, and possibly also in a separate ad hoc document.

According to the Recommendations, when third-party service providers are involved, the tasks delegated to them should be delineated in a specific written agreement with the delegating party.[5]

Informed consent

The procedure for managing and acquiring informed consent remotely for decentralised clinical trials requires special attention. A trial participant must be positioned to receive clear, adequate and fully comprehensible information in order to provide valid consent to participate in the trial.

When the consent process is carried out remotely, the risk that it is not properly executed is higher in all respects. The Recommendations state that the standard should be for interviews between the investigator (or their delegate) and potential participants to be held in person, unless a reason for conducting remote interviews is provided in the protocol and the relevant procedure is described in detail. Of course, the more vulnerable the study population and the higher the risk associated with the investigational drugs and the trial, the more necessary an in-person meeting between participants and investigator is for the purpose of obtaining informed consent.

Further, the Recommendations highly recommend that any remote interviews take place in real time in audiovisual mode. This renders such interactions more useful and gives participants the opportunity to ask questions and seek clarification when necessary.

Finally, when it comes to signing informed consent forms, a paper form is one possibility. When digital tools are used, the signing process must be traceable, and it must be possible to verify its validity. Tools must also comply with the relevant European and national regulations.

Delivery of drugs

Another aspect of remote trials to consider carefully is delivery and administration of drugs at a participant’s home. For example, there are obvious risks in storing products outside of trial centres and asking people other than investigators and their delegates to manage medicinal products. This is particularly true in the case of direct administration by the patient.

For these reasons, the pros and cons of conducting this phase remotely should be carefully assessed. This involves weighing all the relevant elements (such as the suitability of the home, the trial population, the type of drug and the logistical reliability). It is also recommended that the entity assigned to perform delivery be authorised to distribute or dispense medicinal products in the country concerned and enter into a targeted written agreement with the delegating party.

A drug should be delivered only to the trial participant (or their authorised representative) or to a healthcare professional present in the home. There must be procedures in place to verify that the product has been delivered into the hands of the rightful recipient, and the patient must be provided clear and specific instructions for storage and administration of the drug at home (particularly in the case of self-administered drugs).

Data management

Finally, conducting experimental activities remotely involves having subjects, investigators and staff (such as private nurses and third parties in charge of logistics) collect and manage data, while participants may also be called upon to provide experimental data directly by means of wearable digital devices.

This scenario requires specific and adequate measures to ensure that the resulting data is reliable and verifiable, and that participants’ privacy is respected. All parties involved in a trial should be suitably trained and provided with an overview of the flow of collected data. Digital tools used for data collection (which may include medical devices) must be appropriately configured and used in accordance with the law. In addition, measures such as encryption to protect the transfer of data from one device to another or from one device to a server must be in place.

The Italian framework

During the pandemic, the Italian Medicines Agency (Agenzia Italiana del Farmaco or AIFA) issued guidelines[6] for management of clinical trials in an emergency scenario. The guidelines introduced exceptional temporary measures designed to allow, among other things, the remote management of certain trial phases – such as monitoring and home care activities – to ensure that studies would remain ongoing. Application of these guidelines was limited to the period of the Covid-19 emergency, but use of digital tools in clinical trials has constantly increased to the extent that hybrid model is slowly becoming established practice.

With the end of the pandemic period and the expiry of the emergency legislation also adopted for decentralised clinical trials, Italy was left without a specific regulation for DCTs. In the absence of specific regulations, the opportunity to use digital tools for certain remote trial phases has been left to ethics committees and the regulatory authority as part of their case-by-case assessment of individual trial protocols.

The new national guidelines

On 20 August 2024, AIFA issued guidelines concerning the simplification and decentralisation of clinical trials of drugs (‘the Guidelines’). The document was drafted by the Technical Table[7] established by the Italian Ministry of Health to discuss clinical research on drugs. The table’s objectives include formulating proposals for revision of existing regulations and identifying concrete steps to improve the conduct of experimental activities.

The Guidelines address some specific aspects of DCTs in line with the guidance provided at European level by the Recommendations adopted under ACT EU: namely, the roles and responsibilities of the parties, especially when third-party service providers are involved, the delivery of the investigational drug to the participant’s home, and data processing aspects. It is worth noting that the document’s preamble explicitly cites and confirms the ‘full applicability’ of the recommendations developed by bodies and working groups within the EU, including the ACT EU initiative and the relevant recommendation paper on DCTs.

The scope of the Guidelines is limited to clinical trials of drugs. However, they will be applied to other types of studies for aspects not specifically regulated by the law – eg, to observational studies or to clinical investigations of medical devices.

Decentralisation of trials in Italy

The AIFA Guidelines devote ample space to the role and responsibilities of the parties, particularly with regard to the use of third-party service providers to carry out trial-related activities, and the delivery of the investigational drug to the performance of procedures at the participant’s home.

As a general rule, it is recommended that a trial site meets the needs of the procedure through its own resources and capabilities. When this is not possible, the site may enlist the help of third-party service providers, which may be provided by the sponsor. Trial sites also may enter into contracts to outsource certain parts of a trial to service providers, based on criteria established by the sponsor.

It is the sponsor’s responsibility to determine the trial design and its practical organisation, including prior or upon-request engagement of trial sites of third parties (service providers) that can support the work of such sites. This is possible as long as certain basic conditions are met. These conditions include the following:

• The roles and the responsibilities of the sponsor and the trial site must be separate and clearly delineated with respect to management of the third-party provider, the specific tasks required, and how it processes patients’ personal data.
• The duties and responsibilities of the third-party provider must be listed in a written contract between the sponsor and service provider. Engagement of the service provider must be reflected in the contract between the sponsor and the trial site, along with a description of the provider’s powers and duties, including those related to data protection.
• The provider must be adequately trained in the trial protocol and the tasks to be performed as part of research activities.
• The principal investigator must retain ultimate responsibility for all medical decisions and therefore should supervise the provider’s work and receive from the provider any useful information.

Furthermore, for the first time since the pandemic, the opportunity has been provided to deliver investigational drug directly to a participant’s domicile.[8] Although as a rule drugs and devices are sent to the hospital pharmacy by the sponsor, for subsequent delivery to the investigator, the guidelines open up the possibility of home delivery (including through a third-party provider[9]) as long as it is ‘justified on the basis of a specific risk assessment’ (eg, the study design, the condition of the participant, the need for decentralisation and so on) and feasible, depending on the drug involved and its mode of transport, storage, and administration.

As the guidelines do not provide specific information on the storage and administration of the drug at home, the Recommendations could be recalled, according to which, in addition to providing the patient with clear and specific instructions on how to take the drug (especially in the case of self-administered drugs), it is recommended that the investigator regularly checks that the drug is being taken properly and according to the instructions.

Data protection and informed consent management

The new national guidelines pay special attention to the issue of personal data processing carried out by the provider. The provider is identified as a data controller, and is mandated and appointed by the sponsor and/or the healthcare facility to carry out specific activities in support of the trial.

The roles and responsibilities of the parties with respect to data processing should be reflected in the written agreement between the parties. The provider is expected to be duly trained by the data owner and should receive instructions for processing based on the trial protocol. The provider must provide sufficient guarantees and put in place adequate technical and organisational measures for processing in compliance with the General Data Protection Regulation (GDPR) and its implementing rules.

Finally, the new guidelines are silent on the possibility of remote consent, which the Recommendations allow by specifying modalities and guarantees (while generally expressing support for an initial in-person interview). In this regard, other guidelines adopted at national level by the National Coordination Centre for Ethics Committees limit the collection of remote consent to specific situations to be assessed on a case-by-case basis, without providing further indications or reference criteria.