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 (including the language/claims used and whether or not the mention of open-label products is permitted)?

We have not been able to determine any national regulations in this regard. Advertisement for the recruitment of patients seems to be permissible under the EU CTR 536/2014.

Under Annex I –K-59 & K-60 of EU CTR, the following is indicated:

“K. RECRUITMENT ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED)

 59. Unless described in the protocol, a separate document shall describe in detail the procedures for inclusion of subjects and shall provide a clear indication of what the first act of recruitment is. 

60. Where 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.”

9.2 Vulnerable Subjects

The Spanish law does provide for the protection of minors or vulnerable subjects, by allowing for a representative to be appointed on behalf of them. EU CTR has similar provisions.

Art.4 of the Spanish RD 1090/2015 deals with informed consent in case of vulnerable subjects, amongst others. Relevant excerpts of Article 4 are provided below:

“2. Where consent is given by a disabled person, the information shall be made available to him or her in appropriate formats, in accordance with the rules laid down by the principle of design for all, in such a way that it is accessible and understandable to him, and appropriate support measures shall be taken to encourage him or her to give his or her own consent.

3. In the case of minors or persons with modified capacity and to give consent, having given consent to their legally designated representative, when they reach or regain the capacity to consent, their consent shall be sought to continue participating in the clinical trial.

4. The person participating in the trial, particularly in the case of persons with particular vulnerability, shall be informed of the routes of access to routine clinical practice for their pathology.

5. The person participating in a clinical trial, either by himself or with the assistance of his or her legally designated representative, or of the person linked to him or her for family or de facto reasons, may revoke his or her consent at any time, without giving cause and without liability or prejudice for the participant. The withdrawal of consent shall not affect activities carried out on the basis of your consent prior to the withdrawal of consent, while ensuring that neither the data nor the samples obtained on the basis of such consent may be used for analyses or studies after the withdrawal date unless your consent is obtained to make use of them subsequently or, If the purpose is legitimate, the information can be obtained from sources accessible to the public.”

Further, Articles 6 and 8 of Spanish RD 1090/2015 contain provisions regarding clinical trials on ‘people with modified ability to give consent’ and pregnant or breastfeeding women. 

“Art. 6. Clinical trials with people with modified ability to give consent.

1. A clinical trial may only be conducted in adults who are not in a position to give informed consent and who have not given or refused to give informed consent prior to the onset of the absence of capacity, where, in addition to Articles 3 and 4 of this Royal Decree, all the conditions listed in Article 31 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

2. The protocol should be approved by an EMRC which has experts in the disease concerned or which has sought advice from such experts on clinical, ethical and psychosocial issues in the field of the disease and the group of patients concerned.

3. Prior informed consent from the legal representative of the person participating in a clinical trial or the consent of the person associated with him or her for family or de facto reasons, as appropriate, shall have been obtained. In any case, the investigator will reasonably ensure that there are no prior instructions from the person expressed in this regard before submitting a modification of his capacity, having to be respected. This eventuality and the way to proceed must be provided for in the test documentation approved by the CEIm."

“Art. 8. Clinical trials with pregnant or breastfeeding women.

A clinical trial may only be carried out on pregnant or breastfeeding women if, in addition to the conditions laid down in Articles 3 to 6 of this Royal Decree, all the conditions listed in Article 33 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 are met.”

The EU CTR 536/2014 contains similar provisions regarding “specific considerations for vulnerable populations”. Please see Article 10 of the EU CTR.

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

National legislation contains specific provisions for clinical trials on minors. Single parent may sign the consent form if the other parent has provided tacit or express consent to the same, which consent must also be documented. 

Please see Art. 5 of the Spanish RD 1090/2015:

“Clinical trial with minors.

1. A clinical trial on minors may only be carried out if, in addition to the conditions laid down in Articles 3 and 4 of this Royal Decree, all the conditions listed in Article 32 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 are met.

2. The CEIm responsible for evaluating Part II of the assessment report of a clinical trial involving children should have among its members experts in pediatrics or have sought advice on clinical, ethical, and psychosocial issues in the field of pediatrics.

3. Prior informed consent must have been obtained from parents who are not deprived of parental authority or from the minor's legal representative, who shall be heard if, being under twelve years of age, he or she has sufficient judgment. The document of informed consent of the parents will be valid provided that it is signed by one of them with the express or tacit consent of the other that must be sufficiently documented, according to the provisions of article 156 of the Civil Code. When the conditions of the subject allow it and, in any case, when the minor is twelve years or older, he must also give his consent to participate in the trial.”

It is important to highlight the resolution provided within the “Opinion 2/2016 on the impact of the Legislative Reform operated by the RD 1090/2015 of the 04 December 2015 on the intervention of the Public Prosecutor’s Office in Clinical Trials and Biomedical Research”, the conclusion being as follow:

1. Taking into account the legislative reform carried out by Royal Decree 1090/2015, of 4 regulating clinical trials with medicinal products, the Ethics Committees, and the Spanish Registry of Clinical Studies, it is not mandatory to notify the Public Prosecutor's Office of the authorizations clinical trials with minors. 
2. On the other hand, the communication of authorizations related to biomedical research on minors, regulated by Law 14/2007 of the 03 July, is still mandatory, to notify the Public Prosecutor’s Office.

9.4 Financial Disclosures

Art. 32 of the Spanish RD 1090/2015 directs that the ‘economic aspects of the clinical trial’ should be reflected between the sponsor and each clinical trial site. It is required that the clinical trial contract contain the following, amongst other things:

“(a) The initial budget of the trial, which will specify the indirect costs to be applied by the center, as well as the extraordinary direct costs, considering as such those expenses other than those that would have occurred if the subject had not participated in the trial, such as:

1. Analysis and additional explorations added.
2. Changes in the duration of care for the sick.
3. Reimbursement for expenses to patients.
4. Purchase of apparatus and compensation for trial subjects and researchers.

 b) The terms and deadlines of payments.

 c) Any other subsidiary liability contracted by the parties, in accordance with the conditions established in each center.”

Besides the national legislation quoted above, the EU CTR 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.”

Sponsors and Principal investigators are required to complete and submit within the CTA application a “Declaration of Interest” to comply with the EU CTR 536/2014.

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. However, under normal practice, Certificates of Translations (CoTs) are not required to be submitted, but 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?

Articles 9 and 10 of the Spanish RD 1090/2015 contain provisions regarding subject compensation. This is already covered in Section 2.21 of this guidebook.

The sponsor as well as the site has to be listed in the insurance certificate.

In addition to the aforementioned, the AEMPS published on its website Annex VA (Insurance Certificate Model) and Annex VB (Additional Responsibility Commitment in relation to coverage of Clinical trial insurance).

• Duration: Annex VA denotes that the insurance coverage of the trial should be guaranteed for at least one year after the end of the trial. 
• Limits: The minimum limit of insurance is EUR 250,000 per person undergoing the clinical trial, and the maximum limit is EUR 2,500,000 per year per clinical trial.

Annex VB seeks additional commitment by the sponsor, whereby the sponsor shall indemnify not only the subjects of the clinical trial for damages and losses suffered but also the responsibilities of the investigators.

Please see:

1. Annex VA to AEMPS Instruction Document
2. Annex VB to AEMPS Instruction Document