New AIFA guidelines on simplification and decentralization of clinical trials

As mentioned in our other article, this article deals with the guidelines approved by the AIFA on the same day as those on observational studies. They were also published in the Italian Official Gazette on August 20, 2024. The guidelines concern simplification and decentralization of clinical trials of medicines.

The document was crafted by the Technical Table established by the Italian Ministry of Health to discuss clinical research on medicines. Its purview was later extended to medical devices. The table consists of expert researchers, members of regulatory bodies, and representatives of companies in the sector.^[1]

The table’s objectives include formulating proposals for revision of existing regulations and identifying concrete steps to improve the conduct of experimental activities. People in various capacities who support the institutions are included in the discussion.

The new guidelines cover:

• Use of third-party service providers for clinical trial–related activities.
• Reimbursement of expenses and compensation for lost earnings for participants
• Delivery of the experimental drug to participants’ domiciles.
• Allocation of costs related to experimental and ancillary drugs.

Scope and coordination

The scope of the new guidelines is limited to clinical trials of medicines. However, we expect that they will be applied to other types of studies for aspects not specifically regulated by the legislature.

For example, they may be applied to observational studies, as indicated by the new August guidelines on the subject, or to clinical investigations of medical devices.

These guidelines cover several aspects regulated by the now outdated (though never explicitly repealed) Ministerial Decree of December 21, 2007 on administrative procedures for clinical trials. Many of the decree’s provisions are considered outdated because they are not compatible with the provisions of European Clinical Trials Regulation 2014/536. The fact that topics such as reimbursement of expenses and allocation of costs are addressed here as well lends certainty to the regulations.

Decentralization of trials

These guidelines discuss the decentralization of the clinical trials. To date that subject has been mentioned only in documents issued at the European level, apart from a few guidelines provided by the AIFA to manage clinical trials during Covid.

The document’s preamble explicitly cites and confirms the “full applicability” of the recommendations developed by bodies and working groups within the European Union.

The most interesting initiatives include the Act EU (Accelerating Clinical Trials in the EU) initiative and its priority actions. These also deal with the topic of decentralized clinical trials, and they are summarized in the Recommendation paper on decentralized elements in clinical trials adopted in December 2022and discussed in a previous article in this space.

These AIFA guidelines are intended to provide clarification and additional information on organizational aspects in a national context, so that “provisions contained or not expressly prohibited in the European standards and guidelines” can be applied at the national level.

Use of external providers

The AIFA guidelines devote ample space to using third-party service providers to carry out trial-related activities—from delivering the investigational drug to conducting procedures at participants’ domiciles. This may involve using digital instruments (e.g., a hardware/software system for remote data collection) when a trial site cannot handle the work.

As a general rule, it is recommended that a site meet 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. That seems to indicate that a provider can be contracted by both the research center and the sponsor. Study sites also may enter into contracts to outsource certain parts of a trial to service providers, based on criteria established by the sponsor.

Sponsor responsibility

According to the ICH-GCP, it is the sponsor’s responsibility to determine the study design and its practical organization, including prior or upon-request engagement of study sites of third parties (service providers) that can support the work at the centers. 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 study site must be separate and clearly delineated with respect to management of the third-party provider, the specific tasks required, and how they process patients’ personal data—with conflicts of interest strictly avoided;
• The duties and responsibilities of the third-party provider must be listed in a written contract between the developer and service provider. Engagement of the service provider must be reflected in the study contract between the developer and the study 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 study protocol and the tasks to be performed as part of research activities;
• The chief 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.

Delivery of medicines to domiciles

For the first time since the pandemic, the opportunity has been provided to deliver experimental medicine directly to a participant’s domicile. Previously, it was believed that this was not allowed because it was not provided in the Ministerial Decree of December 21, 2007.

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), as long as it is “justified on the basis of a specific risk assessment” (e.g., the study design, the condition of the participant, the need for decentralization, and so on) and feasible and depending on the drug involved and its mode of transport, storage, and administration.

Requirements for foster caregivers

The aforementioned recommendations for decentralized trials developed under Act EU recommend that whenever possible the entity assigned to handle delivery should be an entity authorized to distribute or dispense medicines, and that the medicine should be delivered to the trial participant (or authorized representative) or to a healthcare provider who may be present at the domicile.

The guidelines provide no specific information on storage and administration of the medicine at the domicile. Based on the guidance provided at the European level by the HTA network, in addition to providing the patient with clear and specific instructions for taking the medicine (particularly in the case of self-administered medicines), it is recommended that the investigator check at regular intervals that the medicine is taken appropriately and according to instruction.

Processing personal data

The guidelines pay special attention to the issue of personal data processing carried out by the provider. The provider is identified as a data controller, 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.

For its part, the provider must provide sufficient guarantees and put in place adequate technical and organizational measures for processing in compliance with the GDPR and its implementing rules.

The guidelines say nothing about the possibility of remote collection of informed consent, which the European recommendations of 2022 allow by indicating its modalities and guarantees (while generally expressing support for an initial in-person interview).

At the Italian level, the guidelines of the National Coordination Center for Ethics Committees limit the collection of remote consent to particular situations evaluated on a case-by-case basis, without providing further indications or reference criteria. These guidelines also offer no help on this point.

Reimbursement of participants

The last topic is regulation of reimbursement/allowances for trial participants.

This area has long been tightly regulated by the Ministerial Decree of December 21, 2007, which limited reimbursement options to patients with special or rare diseases (treated in highly specialized centers) and compensation for lost earnings to healthy volunteers only.

This limitation was overcome by the CTR and has been transposed at a national level in an update to the consent form for trial participation available on the National Coordination Center for Ethics Committees webpage, as well as in the guidelines for collecting informed consent.

The new August guidelines further clarify that an allowance for lost earnings may be paid only to healthy volunteers and in the cases provided in Regulation 536/2014 (representatives of incapacitated subjects and minors and pregnant and lactating women).

All information on allowances and reimbursement (disbursement methods and related documentation) must be described in the trial contract and participant information and submitted to the ethics committee for evaluation as part of the documentation in Part II of the trial dossier.

[1] With the decree of January 11, 2024.