April 4, 2023

Decentralized clinical trials: Recommendation paper for the implementation of uniform procedures in the European Union published

The Italian version of this article has been published on March 28, 2023 on AboutPharma.com, within our bi-monthly column “Digital impact in Life Sciences: Legal Corner”.

On December 13, the European Commission (EC), the Heads of Medicines Agencies (HMAs), and the European Medicines Agency (EMA) published a document entitled Recommendation paper on decentralised elements in clinical trials (“Recommendations”) to provide Member States further and more detailed guidance on the implementation of procedures for conducting trials outside of traditional clinical trial centers.

Although the Recommendations are non-binding, they are still a key resource. Indeed, many European countries have yet to adopt specific rules on the subject aside from temporary and exceptional measures introduced during the Covid-19 pandemic[1] to allow studies to continue. In Italy, one of the countries that has not adopted such rules, in the absence of specific regulations on decentralized clinical trials the opportunity to use digital tools for certain remote trial phases is left to ethics committees and the regulatory authority as part of their case-by-case assessment of individual trial protocols. We discussed this in a previous article.

The Recommendations are part of the Accelerating Clinical Trials in the EU (ACT EU) initiative, which was launched in January 2022 to coincide with the full applicability of Regulation (EU) 2014/536 and the Clinical Trial Information System (CTIS). It triggers actions to support implementation of the new trial regulation and strengthen the European ecosystem for modernization and development of trial activities. It has a special focus on clinical trials involving multiple countries and digital technologies. In priority action no. 8, the 2022–2026 work plan of the initiative calls for drawing up guidelines for decentralized clinical trials by the end of 2022, and that deadline was met.

The Recommendations focus on the roles and responsibilities of those involved, the process of acquiring informed consent remotely, delivery and administration of experimental drugs at patients’ homes, and data collection and management.

Roles and responsibilities

When trial activities are conducted outside a trial center, 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.

Again, 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. Furthermore, when a third-party provider is identified by the sponsor and the investigator is not a party to the relevant contractual agreement, the contract between investigator and sponsor should list in detail the tasks delegated to the third party. This allows the investigator to accept or reject assigning certain activities to the third-party provider, or to request additional information about the third-party provider’s qualifications, if the activities fall under the responsibility of the investigator.

Informed consent

The procedure for managing and acquiring informed consent remotely for decentralized 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, it is easier for this purpose to be compromised or not properly executed in all respects.

For this reason, 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. In Italy, where to date there is no specific regulation for managing remote consent collection, the guidelines of the National Centre for the Coordination of Ethics Committees state that consent is ordinarily collected in person with the participant signing a hard-copy form, and that the use of decentralized procedures may be authorized in specific situations and assessed on a case-by-case basis.

Naturally, the more vulnerable the study population and the higher the risk associated with the experimental drugs and the study, the more an in-person meeting between participants and investigator is necessary for the purpose of obtaining informed consent.

Further, the Recommendations highly recommended 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. Additionally, an in-person meeting between the parties should always be arranged when the investigator and/or participants request it.

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[2] and national regulations. Moreover, specific procedures must be set up to manage potential withdrawal of consent electronically.

The delivery and administration of medicines at home

Another aspect of remote trials to consider carefully is delivery and administration of the medicinal product at a participant’s home. For example, there are obvious risks inherent in storing products outside of trial centers 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 medicine, and the logistical reliability). The national regulations of the country of reference must also be consulted. In Italy, for example, the Decree of the Ministry of Health of 21 December 2007 does not allow investigational drugs to be delivered directly to patients’ homes (though AIFA guidelines did make allowances during the pandemic); hospital pharmacies must deliver them to investigators. However, it is possible that mechanisms for delivery to patients in response to specific clinical needs could be allowed.

In that case, it is recommended that the entity assigned to perform delivery be authorized to distribute or dispense medicinal products in the country concerned and enter into a targeted written agreement with the delegating party.

A medicinal product should be delivered only to the trial participant (or their authorized representative) or to a healthcare professional present in the home, and there must be procedures in place to verify that the medicinal product has been delivered into the hands of the rightful recipient.

The patient must be provided clear and specific instructions for storage and administration of the medicine at home (particularly in the case of self-administered medicines). It is also recommended that the investigator check regularly that the medicine is taken appropriately and as indicated.

Data collection and management and monitoring procedures

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. 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 study should be suitably trained and provided 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. Also, 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 more experimental activities are conducted remotely, the more frequently trial progress must be monitored, e.g., checking a participant’s use of digital devices and home medicine storage and management. Monitoring activities may also be carried out remotely rather than in person (at home or at the trial center).

Future perspectives

This document was eagerly awaited by practitioners, who hoped it would clarify certain matters and thus encourage decentralized clinical trials or at least hybrid forms of clinical trials that could better meet the needs of patients.

A few months from now, it will be interesting to see what the concrete impact of these Recommendations is and how much they help to develop a “culture” of remote (as much as possible) experimentation that takes full advantage of the potential offered by technology in this area.

[1] At the European level, see the Guidance on the management of clinical trials during the Covid-19 pandemic, and in Italy the Guidelines on the management of clinical trials during the Covid-19 emergency.

[2] For more detail see the Guidelines on computerised systems and electronic data in clinical trials issued by the EMA.

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