New AIFA guidelines on observational studies and decentralized clinical trials: Digital tools increasingly in focus

August was a busy time on the research activities front. The AIFA issued two new guidelines, focusing, respectively, on observational studies and clinical trials for medicinal products.

The relevant information was published in the Official Gazette on August 20, 2024. First, the AIFA issued the long-awaited guidelines for classification and conduct of observational studies of drugs, in accordance with Article 6 of the Ministerial Decree of Nov. 30, 2021. The guidelines update and replace the previous guidelines issued in 2008. Additionally, new guidelines on regulatory simplification and decentralization elements for conducting drug trials in compliance with the Clinical Trials Regulation were adopted.

These documents address numerous procedural aspects of research, from the process for undertaking and registering observational studies to the rules on reimbursement and compensation for clinical trial participants. Both documents emphasize research activities conducted remotely, outside of healthcare facilities, via digital tools such as wearable devices. Such tools are increasingly used in health care.

We will dedicate the next two columns to these documents, with a focus on digital tools in research activities. Of course, that is the subject of this column, but there are many other points that merit further study.

New guidelines on observational studies – expected impact

A fairly long time after the Ministerial Decree of November 30, 2021, the document updates the outdated 2008 guidelines with a comprehensive overview of the classification of non-interventional studies and the procedures for undertaking and conducting them.

The new guidelines apply to pharmacological observational studies, as did the previous guidelines. However, the AIFA specifies in the preamble that these guidelines can also be used “as a reference” in evaluating nonpharmacological observational studies “in view of the similar methodological approach applied.

This important clarification effectively legitimizes a practice developed in the previous guidelines in the absence of a codified procedure for observational studies not involving drugs.

Of primary importance are medical devices, including software, for which the collection of real-life data is particularly crucial. In the medium- to long-term they can also be used to measure and evaluate actual efficacy and improvement patients’ experience using digital technologies and for pharmacoeconomic evaluation.

Observational studies on devices (i.e., post-certification of the device, employed on the patient according to normal clinical practice) will also use these new guidelines as a reference when applicable (e.g., the obligation to register in the Registry of Observational Studies exists only for pharmacological studies).

The guidelines also clarify that the provisions on clinical trials apply to aspects that are not specifically regulated. This confirms established practice.

Registries and observational studies: Where is the boundary?

Observational study classification depends on when data collection is done versus when the study occurs. Studies may be retrospective (analyzing past events), cross-sectional (data collection and the event occur simultaneously), or prospective (observing events of interest over time as they occur).

Legally, perhaps the most significant distinction is between prospective/cross-sectional and retrospective studies. Study participants in the former generally have the opportunity to express their consent to participate in the studies, whereas retrospective studies are usually carried out on available data and/or biological samples. This raises the question of the legitimacy and limits of secondary use of patient data (or whether further consent needs to be acquired).

It is also interesting that a registry, as a tool for systematic ongoing data collection without a defined endpoint, is not subject to the guidelines (as it is not considered an observational study).

However, a study using registries and real-time data collection classified as an observational study is subject to the guidelines and evaluation by an ethics committee is required. Studies based on secondary use of data contained in registries as part of normal clinical practice and according to authorized indications also fall into this category.

Decentralization of study activities and the role of digital tools

For non-interventional studies, conducting research outside of healthcare facilities can play a key role, given that such studies collect and analyze data about patients already receiving specific therapeutic treatments.

One example is a prospective study that follows patients being treated with a particular licensed and regularly prescribed drug.

If the drug is self-administered, meaning a patient does not have to travel to a healthcare facility to receive therapy, the opportunity to monitor the patient remotely—collecting relevant data and information with digital devices and transmitting it to the practitioners—offers the clear advantage that it is more convenient for the patient. In turn, that leads to the increased likelihood that the study will be conducted successfully.

Digital instruments used for data collection (there are many examples that are medical devices) must be configured appropriately and the use of appropriate measures (such as encryption) to protect data transfer must be ensured. Obviously, they all must be used in accordance with the law.

The new guidelines are the first to recognize explicitly this method of conducting observational studies. They mention that “studies involving the collection of drug therapy data via online platforms, wearables, or other devices may also be considered observational studies” if data on drugs used by patients are analyzed^[1].

Although the same conclusion would likely have been reached earlier, it is a positive step that the possibility of using decentralized procedures and using digital tools in observational studies has been enshrined in black and white. Sometimes the absence of clear rules disincentivizes their use.

Study sites

Consistent with the above, the section on study sites contemplates traditional public and private health facilities, universities, and professional practices. It also establishes the possibility of different sites, such as territorial pharmacies and other health facilities, and of collecting data with digital devices in a decentralized fashion (regardless of where the patient is located)^[2].

All non-traditional sites, including those where data is collected without the direct involvement of qualified medical personnel (e.g., online) must be evaluated in advance by an ethics committee. The committee judges feasibility “with particular reference to the methodology used with regard to compliance with privacy regulations concerning the use of patient data.”

Logically enough, such studies still require written, dated, and signed patient consent to data processing using a consent form reviewed by an ethics committee. We believe that in this case “written” consent can be obtained using digital tools.

The feasibility assessment may involve the AIFA—usually the recipient of a single notification for an observational study—if it is for a post authorization efficacy study (PAES) or post authorization safety study (PASS). Those are undertaken at the request of an authority—the EMA or the AIFA—and coordinated by that authority directly. The authority even approves the facilities involved in the studies.

Consent management

The guidelines do not cover how to collect informed consent for participation in the study. They simply state that the document used is “simplified” compared to the consent document for clinical trials, since treatment involves normal clinical practice. The guidelines also mention that the document must detail the “diagnostic and evaluative procedures” at the core of the study.

There has been much debate about whether informed consent for clinical drug trials can be obtained remotely. At the supranational level there are guidelines on this issue, including those contained in the recommendation paper on decentralized elements in clinical trials adopted by the EMA with the heads of national medicines agencies, which we discussed in a previous article.

The new update of Good Clinical Practice, which is still in draft form, also expressly provides the possibility of collecting consent electronically, as long as the information to be conveyed to the patient is clear and fully comprehensible^[3].

At the national level, the guidelines of the National Coordination Center for Ethics Committees on trial settings, which were updated in May 2022, provide that consent is routinely collected in the presence of the participant by having them sign a paper form, and that the use of decentralized procedures may be authorized in certain situations evaluated on a case-by-case basis.

However, since the AIFA’s new guidelines call for “simplified” methods for observational studies, the feasibility of obtaining consent remotely does not seem to be in question. The guidelines stipulate that the study documentation submitted to an ethics committee should include a “description of the recruitment methods and related methods for acquiring consent to data processing for studies that do not involve the direct involvement of an investigator (e.g., online studies, surveys).”

Data publication

The last item for discussion is the provision that within 12 months of the end of the study a sponsor is required to submit a summary of the study results (even if the results are negative) to the Registry of Observational Studies for publication. As usual, the content of the data submitted should be closely monitored to safeguard intellectual property rights.

[1]Par. 5.4.
[2]Par. 8.
[3]Par. 2.8.