New decrees for the reorganization of ethics committees have been signed: The last fundamental steps for operation of the CTR in Italy

The decrees are the following:

• Decree of the Ministry of Health of January 26, 2023, adopted by agreement of the State-Regions Conference, which identifies 40 territorial ethics committees; these committees are tasked with evaluating clinical trials for medical devices and medicinal products for human use.
• Decree of the Ministry of Health of January 27, 2023, which governs the transitional phase in relation to evaluation activities and the methods for interaction between the coordinating center, the territorial ethics committees (”TECs”), the national ethics committees (“NECs”), and the AIFA, or Italian Medicines Agency (the text is not yet publicly available).
• Regulatory harmonization decree specifically governing the function of the ethics committees, the criteria for division of duties between the TECs and the NECs, and the criteria for composition of the ethics committees.
• Decree, adopted by the Ministry of Health in agreement with the Ministry of Economy and Finance, establishing a single fee for clinical trials.

These are long-awaited decrees in the sector, as they regulate aspects of fundamental importance to procedures envisaged by the CTR. As a reminder, as of January 31, 2023, the CTR is mandatory for all new clinical trials undertaken in Europe (after a year when the procedure envisaged by the CTR was optional).

The TEC identification decree

After thorny negotiations in the State-Regions Conference on the allocation among the various Italian regions of the 40 TECs provided by the Law No. 3/2018, the Lorenzin Law, the decree lists the 40 TECs in Annex I, assigning them the following main duties:

• Evaluation of clinical trials of medical devices and phase I to IV medicines for aspects relating to Part II of the assessment report, as provided in Article 7 of the CTR.
• Evaluation, together with the AIFA, of aspects related to the study protocol included in Part I of the assessment report, as per Art. 6 of the CTR.
• Evaluation of clinical investigations of medical devices and pharmacological observational studies.

The regions have the option of keeping local ethics committees (not included in the list of 40, “local ECs”) operational by appointing their members within 120 days of the decree taking effect. These committees will handle solely functions other than those exclusively attributed to the TECs and the NECs (e.g., for matters concerning the use of medicines, medical devices, the use of surgical and clinical procedures, studies of foodstuffs, and so on).

Conversely, TECs can also perform the functions that local ECs can perform. In other words, at its discretion a clinical center can direct an ethical evaluation request on an issue other than a clinical trial or observational pharmacological study to a TEC or a local EC established in its region.

This decree takes effect 120 days after its publication in order to give the regions time to appoint the members of the local TECs; on the same date, existing TECs will automatically lapse.

The harmonization decree

The content of the decree identifying the 40 TECs must be looked at it in the context of the harmonization decree that divides duties among the territorial and central TECs, completely reworking the entire system. The harmonization decree will replace and expressly abrogate the current Ministerial Decree of February 8, 2013, which has governed the matter for 10 years nearly to the day.

The harmonization decree provides:

• Criteria for the division of duties among TECs, CENs, and local ECs (supplementing the content of the decree on the 40 TECs with further specifics).
• Criteria for the composition of TECs and local ECs, in order to ensure that members have documented knowledge and experience with clinical trials of medicines and medical devices.
• Independence requirements for members of the ethics committees (the report accompanying the decree also specifies that the AIFA measure concerning guarantees to protect the independence of clinical trials and avoid conflicts of interest in the assessment of applications envisaged by Legislative Decree 52/2019 is currently being approved).
• The internal organization of ethics committees.
• Operating mechanisms.

The division of duties between the various ethics committees can be summarized as follows:

• TECs assess clinical trials of medicinal products, clinical investigations of medical devices, and pharmacological observational studies, except in areas under the auspices of the NECs.
• In the fields of pediatrics and advanced therapies, assessment of clinical trials of medicinal products, clinical investigations of medical devices, and pharmacological observational studies remains the responsibility of the respective NECs.
• In the pediatric and advanced therapy sectors, any functions other than those listed in the previous item may be performed by TECs or local ECs, where they exist.
• When established, local ECs may perform all functions other than those listed in (i) and (ii) above.

Finally, with regard to the functioning of ethics committees, the following are of particular interest, and it is expected that when making assessments a TEC will consider the following circumstances:

• In principle, patients in the control group may not be treated with placebos if known effective treatments are available or if the use of placebos results in suffering, prolonging of illness, or risk;
• The right of the investigators who conducted the study to disseminate and publish results must be guaranteed in the trial protocol in compliance with provisions on privacy and patent protection, and there must be no restrictions on the sponsor’s dissemination and publication of the results.

A negative opinion from the TEC or NEC on part II of the dossier shall lead to refusal to conduct the trial nationwide, even in the case of a favorable outcome for part I. In the event that the sponsor appeals a negative opinion, the TEC or NEC is “responsible for managing the appeal procedure, promptly informing the AIFA if the appeal is accepted in order to allow the opinion uploaded in the CTIS to be revised.” No further information on this procedure is provided in the decree and therefore it is not clear at the moment what forms and timing should be applied. However, it is noted that in the event of a refusal, the sponsor may modify study elements by incorporating the committee’s observations and submitting a new application (necessarily) to the same NEC.

Finally, the decree provides that, in the event of inaction or failure to meet deadlines, the National Coordination Center of Ethics Committees shall suggest that the minister of health eliminate the defaulting TEC, and the minister shall proceed with their own decree pursuant to Law 3/2018.