9. Subject considerations

9.1 Clinical trial subject recruitment: Are digital advertisements (including social media streams such as TikTok) allowed and, if so, what regulations govern them? 

Yes, subject to compliance with the appropriate EMA rules. No national regulations are in place to address this point.

Recruitment publicity for clinical trial subjects is covered in Annex I.K of Clinical Trial Regulation (EU) 536/2014, which provides that sponsors, when making their application to conduct a clinical study shall include, for each Member State concerned and unless described in the protocol, “a separate document [that] shall describe in detail the procedures for inclusion of subjects and shall provide a clear indication of what the first act of recruitment is”, and that “[w]here the recruitment of subjects is done through advertisement, copies of the advertising material shall be submitted, including any printed materials, and audio or visual recordings. The procedures proposed for handling responses to the advertisement shall be outlined. This includes copies of communications used to invite subjects to participate in the clinical trial and arrangements for information or advice to the respondents found not to be suitable for inclusion in the clinical trial.”

Whilst the CTR is silent on the specific point of the use of digital advertisements/use of social media, the direct reference to “visual recordings” is considered broad enough to cover this channel. The mention of open-label products would be a matter to be considered during the assessment of the application.

9.2 Vulnerable Subjects 

Recital 15 to the Clinical Trial Regulation (EU) 536/2014 seeks to make a positive case for including vulnerable groups in clinical trials:

“In order to improve treatments available for vulnerable groups such as frail or older people, people suffering from multiple chronic conditions, and people affected by mental health disorders, medicinal products which are likely to be of significant clinical value should be fully and appropriately studied for their effects in these specific groups, including as regards requirements related to their specific characteristics and the protection of the health and well-being of subjects belonging to these groups”.

It goes on to set out in Article 10:

“1. Where the subjects are minors, specific consideration shall be given to the assessment of the application for authorization of a clinical trial on the basis of pediatric expertise or after taking advice on clinical, ethical, and psychosocial problems in the field of pediatrics. 27.5.2014 L 158/19 Official Journal of the European Union EN 

2. Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the application for authorization of a clinical trial on the basis of expertise in the relevant disease and the patient population concerned or after taking advice on clinical, ethical, and psychosocial questions in the field of the relevant disease and the patient population concerned. 

3. Where the subjects are pregnant or breastfeeding women, specific consideration shall be given to the assessment of the application for authorization of a clinical trial on the basis of expertise in the relevant condition and the population represented by the subject concerned. 

4. If according to the protocol a clinical trial provides for the participation of specific groups or subgroups of subjects, where appropriate, specific consideration shall be given to the assessment of the application for authorization of that clinical trial on the basis of expertise in the population represented by the subjects concerned. 

5. In any application for authorization of a clinical trial referred to in Article 35, specific consideration shall be given to the circumstances of the conduct of the clinical trial.”

9.3 Pediatrics (including whether consent from a single parent is sufficient vs. requiring both parents to sign)

Children who have not reached the age of majority (which is 18 in Italy) do not have the right to make autonomous decisions about their medical treatment and require both parents to provide consent.

The Ethics Committees Coordination Center has published on its website parental ICF template as well as mature minor form (12-17 years old) and minor forms (7-11) of ICF.

The Clinical Trial Regulation (EU) 536/2014 sets out in Article 10:

“1. Where the subjects are minors, specific consideration shall be given to the assessment of the application for authorization of a clinical trial on the basis of pediatric expertise or after taking advice on clinical, ethical, and psychosocial problems in the field of pediatrics. 27.5.2014 L 158/19 Official Journal of the European Union EN 

2. Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the application for authorization of a clinical trial on the basis of expertise in the relevant disease and the patient population concerned or after taking advice on clinical, ethical, and psychosocial questions in the field of the relevant disease and the patient population concerned. 

3. Where the subjects are pregnant or breastfeeding women, specific consideration shall be given to the assessment of the application for authorization of a clinical trial on the basis of expertise in the relevant condition and the population represented by the subject concerned. 

4. If according to the protocol a clinical trial provides for the participation of specific groups or subgroups of subjects, where appropriate, specific consideration shall be given to the assessment of the application for authorization of that clinical trial on the basis of expertise in the population represented by the subjects concerned. 

5. In any application for authorization of a clinical trial referred to in Article 35, specific consideration shall be given to the circumstances of the conduct of the clinical trial.”

Article 32 provides for the following:

Clinical trials on minors 

1. “A clinical trial on minors may be conducted only where, in addition to the conditions set out in Article 28 [general rules], all of the following conditions are met: (a) the informed consent of their legally designated representative has been obtained; (b) the minors have received the information referred to in Article 29(2) in a way adapted to their age and mental maturity and from investigators or members of the investigating team who are trained or experienced in working with children; (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is respected by the investigator; (d) no incentives or financial inducements are given to the subject or his or her legally designated representative except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial; (e) the clinical trial is intended to investigate treatments for a medical condition that only occurs in minors or the clinical trial is essential with respect to minors to validate data obtained in clinical trials on persons able to give informed consent or by other research methods; (f) the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors; (g) there are scientific grounds for expecting that participation in the clinical trial will produce: (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or (ii) some benefit for the population represented by the minor concerned and such a clinical trial will pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with the standard treatment of the minor's condition.”

2. “The minor shall take part in the informed consent procedure in a way adapted to his or her age and mental maturity.”

3. “If during a clinical trial the minor reaches the age of legal competence to give informed consent as defined in the law of the Member State concerned, his or her express informed consent shall be obtained before that subject can continue to participate in the clinical trial.”

9.4 Financial Disclosures 

The EU CTR 536/2014 requires the following information to be submitted at the time of submission of the dossier. Please see - Annex I. P of EU CTR 536/2014: 

“69. A brief description of the financing of the clinical trial.

70. Information on financial transactions and compensation paid to subjects and investigator/site for participating in the clinical trial shall be submitted.

71. Description of any other agreement between the sponsor and the site shall be submitted.”

In addition, the European Federation of Pharmaceutical Industry Associations (EFPIA) Code provides for disclosures in relation to clinical studies, as follows (see Annex B on page 37 of the Code), in accordance with clauses 22 & 23.

Clause 23 provides that “Research and Development ToVs in each Reporting Period must be disclosed by each Member Company on an aggregate basis. Costs related to Events that are clearly related to activities covered in this section can be included in the aggregate amount under the “Research and Development Transfers of Value” category”.

Research and Development ToVs are defined in Section 15.01 of the HCP Code as: “Transfers of Value to HCPs or HCOs related to the planning or conduct of (i) non-clinical studies (as defined in OECD Principles on Good Laboratory Practice); (ii) clinical trials (as defined in Regulation 536/2014); or (iii) NIS that are prospective in nature and that involve the collection of patient data from or on behalf of individual, or groups of, HCPs specifically for the study”.

9.5 ICF translations – Are Certificates Required?

The national law is silent on whether or not a translation certification is required. Under normal practice, Certificates of Translations (CoTs) are not required to be submitted. However, relevant CoTs should be filed within the Trial Master File.

9.6 Subject Compensation: Is there a need for a local sponsor to be listed on the insurance certificate, the insurance certificate to cover the duration of the study, and specific minimum amounts of coverage to be specified, both for individual events occurring and in aggregate?

According to the Ministerial Decree of 14 July 2019:

Art 1. “The promoter of the clinical trial must submit to the ethics committee, in accordance with art. 3, paragraph 3 of the legislative decree 24 June 2003, n. 211, an insurance certificate, drawn up in Italian and signed by the insurance company, in application of the current insurance contract, as per the attached standard form which is an integral part of this decree, which explicitly refers to the proposed interventional study, with the description of the elements essential, provided for by this decree…”

Art 2. “The insurance policy must guarantee specific coverage for the compensation of damages caused to subjects by the trial activity, for the entire period of the same, to cover the civil liability of the experimenter and the promoter, without excluding damages involuntarily caused as a consequence of an accidental event and/or attributable to negligence, imprudence or incompetence, provided that they occurred within the periods indicated in the following paragraph 3. 1. The sponsor of the clinical trial must submit to the ethics committee, in accordance with art. 3, paragraph 3 of the legislative decree 24 June 2003, n. 211, an insurance certificate, drawn up in Italian and signed by the insurance company, in application of the current insurance contract, as per the attached standard form which is an integral part of this decree, which explicitly refers to the proposed interventional study, with the description of the elements essential, provided for by this decree. The ethics committee, in issuing its opinion, according to the model/format defined by the ministerial decree of 21 December 2007 (Appendices 6 and 8), takes into account the insurance certificate presented by the sponsor of the clinical trial which is drawn up in accordance with the requirements set out in this decree. If the certificate referred to in paragraph 1 provides for a duration of validity shorter than the actual duration of the trial, the promoter, at each expiry of the validity period of the insurance certificate, is required to present the new renewal certificate to the ethics committee by the date of expected expiry. Notification of the renewal certificate to the ethics committee/competent authority constitutes a non-substantial amendment.”

Art 3 “The terms set out in the policy for the manifestation of the damages referred to in paragraph 6 and for the submission of requests for compensation cannot be less than 24 and 36 months respectively from the date of conclusion of the trial. The date of conclusion of the trial means the last medical-surgical, diagnostic and/or therapeutic service carried out according to the trial protocol relating to the last patient enrolled in Italy.”

Art 4 “In the case of research potentially capable of causing damage that can be seen after a longer period of time, the minimum period of coverage of the posthumous risk referred to in paragraph 3 must be appropriately extended. For research on minors, this extension must provide coverage for at least 10 years, for the time necessary to verify normal psycho-physical development.”