Observational studies: From the November 30, 2021 Decree to the new document of the National Coordination Center for Ethics Committees

The Italian version of this article has been published on August 4, 2022 on AboutPharma.com, within our bi-monthly column on the new Clinical Trials Regulation EU 536/2014.

Pharmacological observational studies concern drugs prescribed according to an authorized therapeutic indication and based on normal clinical practice. Such a study analyzes the effect of a medicine on a group of subjects in order to assess its safety profile under normal conditions of use, confirm appropriate prescription scenarios, and evaluate its pharmacological and economic aspects.

Due to their nature, observational studies do not pose additional risks to patients and therefore need their own specific regulation—different from the regulation for interventional studies—to facilitate and support their implementation. Such studies are a very important part of clinical research, yet they have never been the subject of a full regulation, except for guidelines issued by the Italian Medicines Agency (“AIFA”) in March 2008 (the “2008 Guidelines”).

The (very limited) provisions of the November 30, 2021 Decree

For this reason, the November 30, 2021 Decree (the “Decree”), which, in line with Law No. 3/2018 (known as the “Lorenzin Law”) and Legislative Decree 52/2019, was intended to revise regulations on observational studies in order to facilitate and support their implementation, was highly anticipated. The Decree was finally issued on November 30, 2021 (the same decree governs nonprofit studies) but did not fulfill expectations as it barely touches upon observational studies, instead deferring to the AIFA the issuance of new guidelines for their classification and conduct. The AIFA was supposed to issue those guidelines within 30 days of adoption of the Decree, but they have not yet been published.

The Decree is limited to two provisions regarding observational studies (Art. 6): (i) it states that the submission of observational studies and related documentation must be registered by the sponsor in the Observational Studies Registry at the AIFA, using the forms published in the respective section of the AIFA institutional portal (a page that has not been updated since 2010!); and (ii) it clarifies that prospective pharmacological observational studies can be undertaken only after a favorable opinion, valid for all centers where the study will be carried out, is received from the relevant ethics committee.

Requirements for initiating observational studies

An observational study, like any other clinical trial, always requires the involvement of the relevant sponsor ethics committee, with arrangements differing depending on whether the study is prospective or retrospective.

Regarding prospective studies, while the 2008 Guidelines state that ethics committees (different from coordinating committees) can send any comments to the coordinating committee and communicate their “formal or justified refusal for participation in the study,” under the new Decree the approval of the ethics committees of all participating centers is not required. This will certainly streamline the procedure.

Regarding initiation of retrospective observational studies, the 2008 Guidelines require simple notification by the sponsor of all the ethics committees of the centers involved. A tacit approval mechanism allows the study to begin 60 days after this requirement has been met. The new Decree, however, does not focus on this aspect and considers solely the opinion of the coordinating committee in the case of multicenter prospective studies. For further guidance on how to start these studies, it will therefore be necessary to wait for the new AIFA guidelines pursuant to Article 6(3) of the Decree to be issued, in the hope that the streamlined notification mechanism will be preserved. This proceeding could be further streamlined by requiring the sponsor to notify only a single coordinating center, which would then lead to nationwide acknowledgement.

Forecasts for the start of the study are also to be considered and coordinated with changes that affect the organization of ethics committees in Italy. These also reflect the Lorenzin reform, particularly through the establishment of the National Coordination Center and the identification of ethics committees of national significance. However, a decree that identifies a maximum of forty territorial ethics committees has yet to be adopted. In light of this, it is legitimate to wonder, for example, how the coordinating committee should be identified in the context of a prospective observational study.

Nonpharmacological studies

As pointed out in the document published on July 26, 2022, by the National Coordination Center for Ethics Committees, the category of observational studies is broad and varied in terms of both goals and subject matter. It consists of studies “characterized by the absence of active intervention by researchers… in which the researcher does not determine the assignment of subjects to different study groups, but merely records (observes) what happens in reality.” Specifically, observational studies “may have as their subject of investigation healthy or diseased persons, medicines, medical devices, diagnostic procedures, biological material of human origin, prognostic and predictive factors, genes involved in hereditary diseases, occupational hazards, changes in clinical practice, appropriateness of procedures, and other items.”

Nonetheless, like the previous framework, the new Decree doesn’t take into consideration (as might be expected) observational studies that are not conducted on medicines. As a result, while waiting for guidelines that hopefully will regulate a broader spectrum of observational studies, the practice of using the discipline applied to medicine observational studies for other types of observational studies will most likely continue.

Processing personal data

Another issue is the handling of the health data of subjects included in a study, particularly with regard to retrospective studies, where contacting individuals may be difficult or even impossible because of the amount of time that has passed since the analyzed events took place.

Article 110 of Legislative Decree 196/2003 (the “Privacy Code”) expressly mentions a scenario in which—in the context of processing health data for research purposes—informing the data subjects proves impossible or requires disproportionate effort on the part of the owner. In these cases, processing may waive consent of the subjects if once the relevant ethics committee has issued a favorable opinion the research program is submitted to the Italian Data Protection Authority pursuant to Article 36 GDPR and obtains the necessary favorable opinion.

There are numerous examples of favorable opinions issued by the Italian Data Protection Authority. The latest dates to June 30, 2022, and refers to an observational study aimed at the creation of a database to examine patients suffering from thoracic diseases. In this case, a favorable opinion under Article 110 of the Privacy Code was issued with reference to retrospective collection of data, since many patients were deceased or otherwise unavailable. At the same time, the Italian Data Protection Authority required that specific measures designed to reduce risks for the data subjects and appropriate methods for making the processing public pursuant to Article 14(5)(B) of the GDPR be adopted.

However, application of Article 110 requires following a long and complex path. Streamlining the mandatory requirements would be one way to encourage observational studies. For example, allowing widespread use of alternative legal bases for consent would do away with the need to seek individual opinions and authorizations from the Italian Data Protection Authority on a case-by-case basis. Accordingly, the document of the National Coordination Center for Ethics Committees appears to be in favor of changing the current approach, calling as it does for the elimination of obstacles to the use and reuse of research data. Such changes would include using legitimate interest as a legal basis for data processing, in conjunction with the adoption of appropriate security measures for the protection of data subjects.

Still, in Italy the systematic use of alternative legal bases for consent is hindered by national legislation that continues to position consent as the main source of legalization of treatment and allows it to be waived only in compliance with procedures and fulfillments that are often very difficult to follow in practice.