5. Investigator and Investigational Product

5.1 Does local regulation require PI/CI to be approved/registered by any health authority (e.g., RA/EC)?  

Yes, the investigator must be a doctor.

See Art. 41.2, the Spanish RD 1090/2015:

“2. Only a doctor or a person practicing a recognized profession in Spain may act as an investigator to carry out the investigations based on their scientific training and experience in the required health care.”

See Art 49 of the EU CTR 536/2014:

“The investigator shall be a medical doctor as defined in national law, or a person following a profession which is recognized in the Member State concerned as qualifying for an investigator because of the necessary scientific knowledge and experience in patient care. 

Other individuals involved in conducting a clinical trial shall be suitably qualified by education, training and experience to perform their tasks.” 

5.2 Does local regulation require any specific documents if PI/CI is based outside the country?

Not specified by national regulations.

It is not clear what the position is if the PI is located outside of the EMA. But, unless qualified as per the Spanish laws, a person is unlikely to qualify as an investigator.

5.3 Does local authority allow electronic ICF administration, including electronic signatures?

Yes, Spanish authorities allow the use of electronic consent as well as electronic signatures as long as those are in compliance with the requirements of Advance Signatures as per the eIDAS regulation 910/2014.

Section 13.1.1 Informed Consent on the AEMPS Instruction Document, provides the following information regarding the electronic consents.:

“13.1.1 Informed consent

 As part of the process of obtaining informed consent, it is considered essential that face-to-face communication takes place between the potential trial participant and the investigator, or a qualified person designated by the investigator. If this discussion is done in a digital/virtual meeting, it is recommended that this takes place in real-time where the parties can both see and communicate with each other via audio and video.

 Consent must be obtained, preferably in writing. However, in exceptional and justified circumstances it is permissible to get the consent orally (for example, by telephone or video-call), documenting it in the patient's medical records and ratifying it later in writing by means of the patient's signature and that of the investigator. The principal investigator or the person who has been designated by him/her must send the patient information sheet (PIS) to the patient by email or courier. The later ratification in writing by means of the patient's signature and that of the investigator can be carried out by mail, by audio-visual means, or by digital images. The patient can send the scanned, signed PIS by email, or can take a photo of the signed consent and send it to a telephone only accessible to the research team. This image file must be printed out and maintained in the investigator's file as proof of signature. 

Electronic informed consent is possible as long as it is obtained with a high-security level signature, in accordance with eIDAS Regulation nº 910/2014, and confidentiality and security of personal data, as well as secure access, is guaranteed. Only this type of signature meets the specifications, procedures, or controls to avoid the misuse or alteration of the identity. 

EMA’s “Guideline on computerized systems and electronic data in clinical trials” and chapter 3 of EMA’s “ Recommendation paper on decentralized elements in clinical trials” should be taken into consideration too. The entire procedure for obtaining informed consent should be described step-by-step in the clinical trial application, part II, to ensure appropriate CEIm ethical review.”

5.4 Does local regulation require ICF to be administered as audio/visual and do these need to be recorded?

No, please refer to section 5.3 above for more information.

5.5 Is there any specific information/requirement on data capture/management (e.g., privacy regulations, etc.)?

The EMA published the final Guideline on “Computerized systems and electronic data in clinical trials” in March 2023, becoming effective on the 09^th Sept 2023. 

The purpose of this guideline is to assist Sponsors, investigators, and other parties involved in clinical trials to comply with the requirements of the current legislation (EU CTR 536/2014, Directive 2001/20EC and Directive 2005/28/EC), as well as IHC E6 Good Clinical Practice (GCP) regarding the use of computerized systems and the collection of electronic data in clinical trials. 

EMA’s guidance sets expectations on the handling of electronic data at trial level where for each trial, it should be identified what electronic data and records will be collected, modified, imported, exported, archived, and how they will be retrieved and transmitted. It includes expectations on the audit trail such as accessibility to investigators, monitors, auditors, and inspectors without compromising the confidentiality of participants’ identities. Refer to section 6 for more information on electronic data.

Clinical trials conducted in Spain must comply with the General Data Protection Regulation (EU) No 2016/679, which outlines clear responsibilities for organizations processing personal data, as well as the Spanish “Organic Law 3/2018” related to the Protection of Personal Data guarantee of digital rights.

5.6 Does local regulation allow Home Healthcare Professional Visits (HHCP) in decentralized and/or hybrid studies? If yes, explain if there are any specific requirements to fulfill these obligations.

Yes, according to the response indicated in the Appendix within EMA’s “Recommendation Paper on Decentralized Elements in Clinical Trials”.

Spain's responses to Questions 13 and 14 are shown below:

Question 13: Is it possible for the PI to delegate tasks under their responsibility to a qualified (for the delegated task) external healthcare provider? 

Response from Spanish Authority: Yes*. If adequate investigator oversight and proper contractual arrangements between the sponsor, trial site, and investigator are ensured. Data protection aspects should also be considered. 

Question 14: Certain tasks/procedures carried out at home may require supervision of the investigator (a physician). Is it allowed for the physician to supervise remotely?

Response from Spanish Authority: Yes*. Certain tasks/procedures should be defined in order to provide proper assessment. General Data Protection Regulation (GDPR) should be addressed in this regard. 

5.7 Does local regulation allow Direct-to-Patient (DTP) study product delivery (such as home delivery) in clinical trials? Are there specific requirements to fulfill (e.g., acknowledgment of/signature for the product by the patient, etc.)?

Yes, with exceptions. 

Section 13.1.2 - Delivery of IMPD directly to trial participants - within the AEMPS Instruction Document, provides the following information:

“Direct shipment to patient’s home is not possible without the involvement of a Hospital Pharmacy Service. 

In case trial sites do not have pharmacy services, it will be possible for the sponsor to send the investigational drugs to the research center, with the investigator’s assumption of the responsibilities with regards to handling and shipping of IMP, in accordance with the study protocol specifications. The Pharmacy Departments of hospitals will be able to take the measures they consider necessary, for example, the dispensing to a person authorized by the trial patient of a treatment that must be taken at home or the sending from the Pharmacy Department of the treatment to the patient’s home when their circumstances make it advisable. With regard to the latter, preservation of the treatment must be ensured during transport, and communication with the patient, allowing treatment reception and appropriate administration of the same must be maintained. 

In the exceptional case that, being necessary, the Pharmacy Department cannot send the trial treatment to the patient’s home, said Department might consider other alternatives and entrust the sponsor to organize dispatch via an authorized drug distributor. 

Direct shipment to the patient’s home by the Pharmacy Service shall be stated in the authorized clinical trial protocol and must be adequately documented during the trial course.”

5.8 If a clinical study involves the study product as OTC and this is provided via pharmacy/Amazon, etc., are there any specific regulations for IP management that need to be followed?

Yes. Please see below the definition and requirements for Auxiliary Medicinal Products (AMP). 

The EU CTR does not mention OTC but instead, they use the term of Auxiliary Medicinal Product (AMP), which is defined in Art 2 (8) as “ a medicinal product used for the needs of a clinical trial as described in the protocol, but not as investigational medicinal product”.

As such, AMPs used within a clinical trial will observe the same requirements as the investigational medicinal products.

5.9 For a marketed study product/OTC, can a participant be compensated after confirmation of the purchased study product, or upfront prior to product acquisition? Does compensation in any way impact how the study is viewed (i.e., RWE vs. Interventional Study)?

National provisions do not directly address this issue. However, an exception from such compensation obligation does appear in Article 39.3(g), Spanish RD 1090/2015.

Art. 39.3. “The sponsor’s responsibilities are … (g) Ensure that the participation of a subject in the clinical trial will not imply a cost for him in addition to what he would have had to face in the context of usual clinical practice.”

5.10 Is it permitted to pay participant stipends (i.e., is it permitted to pay the patients for their participation in the clinical trial)? If so, what is the average range?

Yes, Compensation is permitted under certain conditions, subject to the applicable laws.

Chapter II, Article  3.1 (h) of the Spanish RD 1090/2015 states the following:

“h) No undue influence, including that of a financial nature, is exerted on trial subjects to participate in the clinical trial. 

In this regard, subjects participating in trials with a potential direct benefit for the subject or their legal representatives may only receive reimbursement from the sponsor for extraordinary expenses and losses of productivity resulting from their participation in the trial. In special situations, the CEIm may report favorably on compensation of trial subjects for the discomfort resulting from their participation in said trial, provided that it is ensured that such compensation does not influence the decision of the subject to participate in the study.”

Additionally, Article 32.3 (a) of the Spanish RD 1090/2015 requires that the clinical trial agreement between the sponsor and trial site shall have a provision for “reimbursement of expenses to patients”, amongst other matters.

5.11 Specific labeling requirements for clinical study product

Article 35 of the Spanish RD 1090/2015 sets forth the requirements for labeling. But in its content, the legislation simply provides further reference to Articles 66-68 of the EU CTR 536/2014. Nonetheless, it states that the labeling must appear at least in the Spanish language. 

“Art.35. Labeling

1. The labeling of investigational or auxiliary medicines shall comply with what is indicated in articles 66 to 68 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014, taking into account what is established in the detailed guidelines of the correct manufacturing standards applicable to medicines under investigation in the European Union and, where appropriate, the instructions of the Spanish Agency for Medicines and Medical Devices.

2. Except for justified exceptions, it must appear at least in the official language of the State.”

Articles 66-68 of the EU CTR 536/2014 state the labeling requirements of investigational drug products, both authorized and unauthorized. These articles further refer to Annex VI of the EU CTR 536/2014 which contains detailed provisions on the labeling requirements.

5.12 What documents need to be submitted (including relevant fee if any), and to whom, if a permit is needed for an investigational/study product being shipped from outside the country? Are there any specific requirements for biologics?

An application for import authorization request needs to be filled in. Please refer to Section 2.6 of this guidebook for further information.

Section 12.4 Import/Export of Investigational Medicinal Products within the AEMPS Instruction document for conducting clinical trials in Spain_v19_24Nov2023 indicates the following:

12.4.1. Import 

“The request for authorization of investigational medicinal products shall be submitted by a importer lab duly authorized to conduct importation activities of investigational medicinal products and in accordance with the provisions of Royal Decree 824/2010, of June 25th, regulating pharmaceutical laboratories, manufacturers of active ingredients for pharmaceutical use and foreign trade in medicines and medicines under investigation. 

The import authorization for investigational medicinal products for human use for clinical trials authorized in Spain, as well as their intermediates and bulk products, may also be requested by the sponsor, as soon as provisions of point 1.2.4 of Circular 1/2015 on foreign trade in medicinal products are met. 

These import requests shall be submitted through ECM Portal, accessible through the AEMPS website, attaching the completed Annex III of Circular 1/2015, until the electronic pathway that contemplates the complete procedure is available. For investigational medicinal products for clinical trials authorized under Regulation 536/2014, submitted via the CTIS Portal, import authorization requests will be sent to the Clinical Trials Division via email at aecaem@aemps.es , attaching Annex III, until the electronic pathway that contemplates the complete procedure is available. 

It is possible to request the import authorization together with the trial authorization application, but it will be conditioned to the prior authorization of the trial.

 All of the above is also applicable to investigational medicinal products without marketing authorization for clinical trials not authorized in Spain, when they have been previously used in a clinical trial authorized in Spain. 12.4.2.”

5.13 What is the turn-around time to get an import permit?

Sixty days - Please see Article 34.7, of the Spanish RD 1090/2015:

“7. The authorization for the importation of investigational medicinal products for use in the context of a clinical trial shall be considered as granted if within sixty calendar days from receipt of the application, the Spanish Agency of Medicines and Medical Devices has not notified any reasoned objections to the sponsor, provided that the trial is authorized."

5.14 Does local authority allow the destruction of clinical supplies at an off-site location (e.g. third-party vendor in or outside the country) after study completion? Are certificates of destruction required?

The matter of destruction is not stated in national regulations. However, Spanish RD 1090/2015 allows for the continued use of a drug in Spain after the end of trial, for both drugs marketed in Spain and drugs without marketing authorization.

Please see the relevant provisions of the Spanish RD 1090/2015 as under:

“Art. 31. Continuation of treatment with a drug without marketing authorization in Spain after the end of the trial.

Any continuation in the administration of a drug under investigation without marketing authorization in Spain to subjects who have completed their participation in a clinical trial, as long as the drug is not effectively marketed in Spain for those conditions of use, will be governed by the rules established in the Royal Decree 1015/2009 of June 19, which regulates the availability of medicines in special situations. The supply of said medicines must comply with the provisions of paragraph f) of article 39.3, if the sponsor obtains any information on the administration and use of said medicine under these conditions.

“Art. 37. Surplus medication from a clinical trial.

1. In the case of investigational medicines and auxiliary medicines marketed in Spain, once the clinical trial has finished, those remaining unaltered containers may be used in normal clinical practice, under the conditions stipulated in their marketing authorization, that is, that have not been modified in their primary or secondary packaging, and always under the express and prior authorization of the sponsor.

2. In the case of investigational drugs not marketed in Spain, once the clinical trial has finished, the sponsor may request the use of unaltered leftover containers for the continuation of treatment outside the trial in accordance with the provisions of article 31.”