2. General Questions

2.1 Name of Regulatory Authority

"Spanish Agency for Medicines and Medical Devices / Agencia Española de Medicamentos y Productos Sanitarios (“AEMPS”)"

The AEMPS is the Spanish competent authority in charge of ensuring the quality, safety, efficacy, and correct information of medicines and health products, for human and veterinary use, in clinical development and on the market.

AEMPS is also designated as the national contact point under the EU CTR, as it handles all communications via the Clinical Trial Information System (CTIS) for Spain. 

Please see Art. 46 “Information Systems” of Spanish RD 1090/2015

2.2 Name of Ethics Committee

There are multiple Ethics Committees recognized in Spain, which are eligible to evaluate clinical trial applications.

The AEMPS publishes on their website those CEIms that can take part in the CTIS review. It is recommended to view the list on the “Castellano” settings, as the English part of the AEMPS website is not always up to date.

An updated list of Ethics Committees recognized by the AEMPS is available here. 

Note: The Ethics Committee is referred to as CEIm in the Spanish legislation text (short for Comité de Ética de la Investigación con medicamentos). Hence, the term ‘CEIm’ appearing hereafter, should be interpreted to mean the Ethics Committee.

2.3 Clinical Trial Application Language

English OR Spanish

The Instruction Document of the AEMPS for Conducting Clinical Trials, version 19, dated November 24, 2023, English version published on 27^th November 2023 provides further reference to the Q&A Document of EudraLex Volume 10, Chapter V for matters pertaining to applications on CTIS. 

Upon reading the relevant parts of the said Q&A Document, i.e., annex II (available under Chapter V – Additional Documents > Questions and Answers Document  Regulation (EU) 536/2014, it is indicated for Spain that  submission of Part I documents may be made in “EN or ES” (except labeling, which should be in Spanish), with a clarification note stating that “for documents for which EN OR national language can be chosen, only ONE language version of the documents should be submitted.”   

Annex 1 to the AEMPS Instruction Document provides further clarification on the language requirements for Part I and Part II, see below: 

All part I documents may be submitted in English. However: 

• The application form should contain the information provided in the free text fields in Spanish and English as it supplies the data for the Spanish Clinical Studies Registry (REec). 
• The protocol summary must be submitted in Spanish.
• As a rule, the labeling must be in Spanish, though multilingual labeling is acceptable. The availability of labeling in another language may be assessed, provided the sponsor justifies the difficulty of having the labeling in Spanish and the labeling in another language shall not cause confusion in the distribution and administration of the medicinal product.
• The part II documents addressed to the trial subjects and assessed by CEIm must be written only in Spanish. However, if requested, the sponsor shall be responsible for providing an accurate translation of this information into other languages. These translations do not need to be submitted to the CEIm.

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

Yes, approval from both the Ethics Committee and the Regulatory Authority (i.e., AEMPS) is required.

Article 11.2, RD 1090/2015 states the following:

“The Spanish Agency of Medicines and Medical Devices shall facilitate the assessment procedure and issuing of an opinion by the CEIm in clinical trials with medicinal products in order to integrate the assessment of one and the other into a single opinion per clinical trial, valid throughout the Spanish State. For the integrated assessment to be positive, the assessment by the Spanish Agency of Medicines and Medical Devices and the opinion of the CEIm must both be positive.”

Once a positive opinion is received from both authorities, the clinical trial can be initiated.

For a clinical trial to commence, the prior approval of CEIm and the AEMPS shall be required, along with a clinical trial management agreement between the sponsor and the clinical trial site.

Art. 17, RD 1090/2015 provides the requirements for the conduct of clinical trials:

“Requirements for conducting clinical trials.

1. Clinical trials on medicinal products shall be subject to prior authorization by the Spanish Agency for Medicines and Medical Devices, following a scientific and ethical evaluation of Parts I and II.

2. In order to start a clinical trial with medicinal products in an establishment, the following shall be required:

a) The favorable opinion issued by a CEIm of the national territory in accordance with the provisions of Article 24 that will be unique and binding.

b) The resolution of authorization of the Spanish Agency of Medicines and Medical Devices.

c) The agreement of the management of the participating center which shall be expressed by signing the contract between the sponsor and the center referred to in Article 32. Only in clinical trials in which the sponsor/investigator belongs to the center and no contract signature is required will the express agreement of the management of the participating center be required.

This contract may be formalized at any time and will be effective when the clinical trial is authorized by the Spanish Agency of Medicines and Medical Devices and has the favorable opinion of the CEIm to carry out the trial in the said center.”

2.5 Can regulatory authority and EC submission be done in parallel?

Yes. A single application submission for Part I (intended for AEMPS review) and Part II (intended for the EC review) is possible through the EMA CTIS portal.

Both the EC and AEMPS are responsible for the validation and evaluation of the clinical trial application. The Spanish RD 1090/2015 divides the responsibility for validation of Part I to the AEMPS and of Part II to the EC. Likewise, the evaluation of Part I is to be done by the AEMPS, and of Part II by the chosen EC. Thereafter, the head of AEMPS shall announce the resolution on authorizing the clinical trial, authorizing it with conditions, or rejecting the application.

Articles 21-25, of the Spanish RD 1090/2015 deal with the process of submission, validation, and evaluation of the clinical trial application. 

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

The legislative framework of Spain mandates that authorization be obtained for the manufacture and/or import of drugs under investigation.

Spanish RD 1090/2015 states, as under:

“Art. 34. Manufacture and import of drugs under investigation or auxiliary drugs.

1. The manufacture and importation of investigational medicines for their use in the context of a clinical trial can only be performed by manufacturers and importers of medicinal products that have the appropriate authorization in accordance with the provisions of Royal Decree 824/2010, of June 25, regulating pharmaceutical laboratories, manufacturers of active substances for pharmaceutical use and foreign trade in medicinal products and investigational medicinal products.”

Relevant provisions regarding the application, evaluation, and authorization for the manufacture or import of investigational drugs are covered in the Spanish Royal Decree 824/2010 of 25 June 2010 (“RD 824/2010”), and provided as under:

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

12.4.1. Import 

“The request for authorization of investigational medicinal products shall be submitted by an 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 the 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.”

2.7 Biological Specimen Export Requirements

Export of biological specimens is permitted, subject to the applicable national laws.

The export and import of biological specimens is governed by provisions of Royal Decree 65/2006 of January 30, which establishes requirements for the import and export of biological samples (“RD 65/2006”). 

This piece of legislation covers the following aspects:

1. the custom facilities through which entry and exit of biological samples is permitted;
2. overall requirements for import/ export;
3. voluntary registration with the Registry of Importers and Exporters, created in the Ministry of Health and Consumption;
4. Violation and penalty for violations.

Additional Information on the export and import requirements of biological samples, can be found on the Spanish Ministry of Health website, which provides links to the relevant forms and requirements for registration, see also below:

Registration of importers and exporters of biological samples

Importers or exporters of samples who regularly carry out import or export operations of biological samples may apply for registration in the voluntary register of importers and exporters of biological samples using the specific forms for the registration of importers or exporters of biological samples, available on the electronic headquarters of the Ministry of Health.

This application must be accompanied by the following documentation:

• Annex III duly signed and stamped by the laboratory of origin, identifying the shipment, its characteristics, and the possible health risk, if any, or the Application for Registration document.
• If these samples are part of a clinical trial, registration must be requested by the sponsor of the trial, or where appropriate, its representative or a CRO, providing a letter of delegation of powers from the sponsor and the authorization of the Clinical Trial by the AEMPS.
• Accreditation of the importer's activity: the importing body must be sufficiently accredited according to its activity and comply with the occupational safety regulations applicable to these samples.

Importers and exporters registered in this Registry must renew the documentation every five years or update it when there is a change in the type of sample to be imported or exported or in the centers or countries and must submit a new application form for updating the Registry Update Document.

Failure to renew, as well as any variation in the type of samples, centers, and countries not authorized, will result in removal from the Register of Importers and Exporters.

Once the application for registration or update of the registration has been reviewed and all the necessary documentation has been provided, a resolution will be issued granting or, where appropriate, denying the incorporation in the register, a resolution that will be made available to the interested party on the electronic headquarters of the Ministry of Health.

Additionally, it is recommended to complete and submit within Part II of the application dossier the Annex XIII form, to establish regulatory compliance for the Management of Biological Samples.

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?

Yes, this is permitted.

The primary legislation pertaining to GMOs in Spain are:

1. Law 9/2003, of April 25, which establishes the legal regime for confined use, voluntary release, and commercialization of genetically modified organisms (“Law 9/2003”); and
2. Royal Decree 178/2004, of January 30, which approves the General Regulation for the Development and Execution of Law 9/2003 ("RD 178/2004”). 

The Ministry for the Ecological Transition and the Demographic Challenge (MITECO) has set out the rules and relevant procedures for carrying out clinical trials involving GMOs. 

Based on the type of clinical trial or what the GMP consists of (e.g., human cells, viral vector, etc.), the relevant set of application forms and supplementary documents can be chosen. 

2.9 Is in-country sponsor presence/representation required?

Yes. The Sponsor should be established in Spain or in any other country within the EU. If the sponsor is not established in the EU, the Sponsor needs to establish a legal representative within the EU.

Article 39.1 of RD 1090/2015 states as follows: 

“1. The sponsor, or his/her legal representative, must be established in one of the Member States of the European Union.”

Article 74, of the EU Clinical Trial Regulation 536/2014 reads as follows: 

“1.   Where the sponsor of a clinical trial is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication to that legal representative shall be deemed to be a communication to the sponsor.

2.   Member States may choose not to apply paragraph 1 as regards clinical trials to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.

3.   As regards clinical trials to be conducted in more than one Member State, all those Member States may choose not to apply paragraph 1, provided that they ensure that the sponsor establishes at least a contact person in the Union in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.”

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country?

Yes, a local investigator is required.

See Article 49, 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”.

Art. 41.2, RD 1090/2015 states as under:

“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.”

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator?

No, under the EU Clinical Trial Regulation, there is no role for Chief or Coordinating Investigator, only Principal Investigator and Investigator.

Article 73, of the EU CTR 536/2014, indicates the role of the Principal Investigator as:

“A principal investigator shall ensure compliance of a clinical trial at a clinical trial site with the requirements of this Regulation. The principal investigator shall assign tasks among the members of the team of investigators in a way which is not compromising the safety of subjects and the reliability and robustness of the data generated in the clinical trial at that clinical trial site.” 

A principal investigator is defined in Art 2 of the Spanish RD 1090/2015 as “An Investigator who is the responsible leader of a team of investigators who conduct a clinical trial at a clinical trial site”, whilst an investigator is defined as “An individual who is responsible for the conduct of a clinical trial at a clinical trial site.” 

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled?

A written contract is required between the sponsor and the CRO, delegating authority. The contract does not need to be notarized and/or apostilled.

Article 71, EU CTR 536/2014 provides clarification on the sponsor's role:

“Sponsor

A clinical trial may have one or several sponsors.

Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution or an organization. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial. The investigator and the sponsor may be the same person.”

The intent of EU CTR 536/2014 is replicated in the national legislation of Spain. Article 39.4 of the RD 1090/2015 states that “the sponsor of a clinical trial may delegate all or part of its tasks to an individual, contract research organization (CRO), institution or body, which must have a quality assurance and control system.”

2.13 Is there a requirement to register clinical trials on a local registry or database?

Yes. Besides the registration of clinical trials on the EU database, these must also be registered on the Spanish Registry of Clinical Studies (“Registro espanol de estudios clinicos” or “REec”).

Registration of clinical trials within the EU Clinical Trials Register and CTIS at EMA level, the AEMPS also maintains a Spanish Registry of Clinical Studies (the “REec”), which the Sponsor must update from time to time. 

In the case of trials authorized based on the EU CTR 536/2014, the data that is automatically published in REec from the CTIS platform are trial title, disease investigated, objectives, variables, selection criteria, and the trial dates reported by CTIS. 

The only information that must be included directly in REec, through the person responsible for the study, is that related to the management of the sites.

Relevant excerpts from the Spanish RD 1090/2015 regarding REec are provided below:

“Art. 47. Spanish registry of clinical studies.

1. The Spanish Agency for Medicines and Medical Devices shall maintain a registry of clinical studies with medicinal products for human use on its website.

2. The REec will include the following information:

1. Compulsorily, clinical trials with medicinal products for human use that are authorized by the Spanish Agency for Medicines and Medical Devices, in accordance with this Royal Decree.
2. Compulsorily, non-interventional post-authorization studies that are to be conducted and have been classified by the Spanish Agency for Medicines and Medical Devices.
3. Voluntarily, like other similar databases, other types of clinical studies sponsored by national or international, public or private entities, provided they have at least one participating site located in Spain that includes cases or, not yet including cases, has a Spanish contribution that is considered significant.

3. The registration of a trial or clinical study in the REec will be compatible with its inclusion in other national or international registries. The REec will include prospective information in its scope of application from its start-up.

4. The REec will include for each study the information listed in the Annex, which includes the set of data required in the international platform for clinical trial registries of the World Health Organization. The Spanish Agency for Medicines and Medical Devices will publish the correspondence between these fields and those of the clinical trial authorization request form sent to it in the case of clinical trials with drugs, as well as those of the study classification request form observational studies.

5. In all cases, the sponsor must make public in this register the results of the registered studies once concluded. This shall be done in accordance with the standard and the timelines indicated in the European Commission guidelines and, where appropriate, in the instructions published by the Spanish Agency for Medicines and Medical Devices.”

Art. 48. Procedure for the publication of a study in the REec.

“1. The REec aims to provide reliable and comprehensible information for the general public so the information contained in some fields may be limited in length and must be written in simple language and accessible to citizens without special scientific knowledge.

In order for the REec to be included in the International Platform for Clinical Trials Registries of the World Health Organization, all the information will be available in Spanish and English.

2. The sponsor will be responsible for the quality, accuracy, and regular updating of all study information included in the REec. The Spanish Agency for Medicines and Medical Devices will verify that the data is complete and adequate for its objectives before including it.

3. The registration of the study must be processed, in any case, after having obtained all the authorizations that proceed according to current regulations and before the inclusion of the first subject in it, regardless of whether the study has been previously registered in another public registry, included or not in the International Platform for Clinical Trials Registries of the World Health Organization.

4. In general, the publication of clinical studies will be carried out in accordance with one of the procedures established in sections 5, 6, and 7.

5. Information on clinical drug trials, common to the European Union Clinical Trials Registry, will be published by the Spanish Agency for Medicines and Medical Devices at the time of trial authorization. The sponsor of a clinical drug trial will have a maximum period of fourteen calendar days from the notification of this authorization to complete the necessary additional information in the REec, with a brief summary about the trial and participating centers.

6. For the registration in the REec of observational post-authorization studies, the sponsor will include the data of the study before it starts or within a maximum period of fourteen calendar days after obtaining the corresponding authorizations according to current regulations for those studies that require prior authorization.

7. The sponsor of the type of studies contemplated in article 47.2.c) may voluntarily opt for the registration of their data in the REec once the study has a favorable opinion from a CEI and, where appropriate, the corresponding administrative authorization. The opinion of the CEI will be sent to the Spanish Agency for Medicines and Medical Devices when requesting registration in the registry.

However, the Spanish Agency for Medicines and Medical Devices reserves the ultimate power to verify the information received and admit its publication in the "REec" or, in the event that the information cannot be validated, not to include it.

In any case, the Spanish Agency for Medicines and Medical Devices will publish a document that lists the rules to be fulfilled for the registration of studies in the REec.

8. The Spanish Agency for Medicines and Medical Devices may decide to make public partial information on a clinical trial or an observational post-authorization study in which the sponsor has failed to comply with the information submission deadlines, expressly stating the data of the sponsor as well as the reasons why the registry information is partial. And this regardless of the exercise of those sanctioning actions that may take place, in application of current legislation.

9. It is the sponsor's responsibility to periodically update the information included in the REec. This update will be mandatory regarding the start date of the study in Spain, the participating centers, the end date of the recruitment in Spain, the substantial modifications that entail a change in the data included in the registry and the end date of the study in Spain. The update will be carried out globally and, in any case, on an annual basis until the conclusion of the study and the publication of its results.”

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

25 years from the end of the clinical trial, in digital or paper format.

See Article 58, EU CTR 536/2014:

“Archiving of the clinical trial master file

Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national law.

The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities.

Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article.

The sponsor shall appoint individuals within its organization to be responsible for archives. Access to archives shall be restricted to those individuals.

The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph.

Any alteration to the content of the clinical trial master file shall be traceable.”

See also, Article 43.2, of the Spanish RD 1090/2015:

“1. The clinical trial master file will comply with the provisions of articles 57 and 58 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014. Its content must take into account the supplementary guidance in this regard published by the European Commission.

2. The sponsor and the investigator will keep the content of the master file in paper or digital format of each clinical trial for at least twenty-five years after the end of the trial, or for a longer period if so provided by other applicable requirements, as in the in the event that the study is presented as a basis for the registration of a drug in which annex I of Royal Decree 1345/2007, of October 11, or an agreement between the sponsor, the researcher, and the center must be complied with.

3. The content of the master file will be kept in such a way that it can be easily made available to the competent authorities, should they request it.

4. The clinical history of the trial subject must be kept in accordance with the provisions of Law 41/2002, of November 14, and in accordance with the maximum period allowed by the hospital, institution or private practice.

5. Any transfer of ownership of the master file content will be documented and the new owner will assume the responsibilities set forth in this article.

6. The sponsor will name the people in his organization responsible for the files and access to them must be limited to the designated people.

7. The supports used to preserve the essential documents will be, in general, in electronic format and must guarantee that the documents remain complete and legible during the planned period of conservation and that they are available to the competent authorities in the event that they request them. Any modification of the records must be traceable, allowing the initial and corrected data to be known, as well as the date and signature of the author.

This documentation must be filed, preferably grouped by protocol, in a place that guarantees the confidentiality of the information during the required filing time.

In the event that there are open judicial processes, the essential documents will be kept until there is a final judicial decision.”

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

Periodic safety reporting is required by both the EU CTR 536/2014 and the Spanish RD 1090/2015. Timelines for reporting:

• Adverse events - as specified in the study protocol.
• Serious Adverse events - 24 hrs
• ADRs - 7 days
• SUSARs - Life-threatening - 7 days; Not fatal - 15 days

Detailed provisions are provided below.

Articles 41 & 42 of the EU CTR 536/2014 relate to reporting of adverse events, serious adverse events, and reporting of SUSARs.  

In addition to the EU CTR 536/2014 provisions, the Spanish laws, through its RD 1090/2015 contain the following provisions:

“Art. 49. Obligations of researchers in the registration and communication of adverse events.

1. The Investigator will record and document any adverse events or abnormal laboratory results deemed critical to the safety assessment by the protocol and communicate them to the Sponsor in accordance with the reporting requirements and within the timeframes specified in the protocol, in accordance with as indicated in article 41 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014.

2. The investigator will notify the sponsor of serious adverse events without undue delay and within 24 hours of becoming aware of such events, unless, for certain serious adverse events, the protocol provides that a report is not required. immediate communication. The investigator, when appropriate, will send the sponsor a follow-up report to allow him or her to assess whether the serious adverse event has an impact on the benefit-risk ratio of the clinical trial. In the initial communications and in the follow-up communications, the trial subjects will be identified only by the identification code of the subject in the trial, specific to each one of them.

3. In the event that the death of a subject participating in a clinical trial has been reported, the investigator will provide the sponsor and the CEIm with all the additional information requested.

4. If the investigator becomes aware of a serious adverse event that has an alleged causal relationship with the drug under investigation, which has occurred after the end of the clinical trial in a subject treated by him, he will notify the sponsor of said serious adverse event without undue delay. 

5. In any case, what is specified in the European Commission guidelines or, where appropriate, in the procedures established in the instructions for conducting clinical trials in Spain published by the Spanish Agency for Medicines and Medical Devices must be taken into account.”

Art. 50. Other obligations of the sponsor in the registration, evaluation, and communication of adverse events.

1. The sponsor will keep a detailed record of all the adverse events that are communicated to him by the researchers. These adverse events will be submitted to the Spanish Agency for Medicines and Medical Devices when requested.

2. The sponsor has the obligation to continuously evaluate the balance between the benefits and risks of the trial, which includes a continuous evaluation of the safety of investigational drugs using all the information available to them. Likewise, you must communicate without undue delay within 15 calendar days to the Spanish Agency for Medicines and Medical Devices and the CEIm, by the means indicated in article 21, any information that significantly affects the benefit/risk ratio of the product. trial, with the exception of suspected serious and unexpected adverse reactions that will be communicated in accordance with article 51. Said communication will be made in accordance with Commission or, where appropriate, with the procedures established in the instructions for conducting clinical trials in Spain published by the Spanish Agency for Medicines and Medical Devices.

3. The sponsor must promptly communicate to the investigators any important information that could adversely affect the safety of the subjects or the conduct of the trial. The communication of such information will be concise and practical. The communication will comply with the criteria and the procedure specified in the guidelines of the European Commission.

Art. 51. Notification of suspected serious and unexpected adverse reactions to the Spanish Agency for Medicines and Medical Devices.

1. The sponsor will notify the Spanish Agency for Medicines and Medical Devices of all suspicions of serious adverse reactions and, at the same time, unexpected, associated with investigational medicines of which he has become aware, which have occurred in the clinical trial, whether they occur in Spain or in other countries. Additionally, suspected serious and unexpected adverse reactions occurring outside the trial will be reported in accordance with the criteria established in the European Commission guidelines.

2. In all cases, said notification will be made through the European Eudravigilance_CTM database. 

3. The period for notification of suspected serious and unexpected adverse reactions by the sponsor to the Spanish Agency for Medicines and Medical Devices will depend on the severity of the reaction and will be determined as follows:

1. In case of suspected serious and unexpected fatal or life-threatening adverse reactions, as soon as possible and, in any case, within 7 days after the sponsor became aware of the reaction.
2. In the event of suspected serious and unexpected adverse reactions that are not fatal or life-threatening, no later than 15 days after the sponsor became aware of the reaction.
3. In case of suspected serious and unexpected, fatal or life-threatening adverse reactions, which were not initially considered as such, as soon as possible and, in any case, no later than 7 days after the sponsor has knowledge that the reaction is fatal or life-threatening. 

When necessary to guarantee rapid notification, the sponsor may make an initial incomplete notification that must be completed as far as possible within the following 8 days.

4. The notification of serious and unexpected adverse reactions by the sponsor to the Spanish Agency for Medicines and Medical Devices will be adjusted, in any case, to the criteria and procedure specified in articles 42, 45, and 46 of the Regulation (EU) No. 536/2014 of the European Parliament and of the Council, of April 16, 2014.”

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

A safety report is required annually.

Article 43, EU CTR 536/2014:

“1.   Regarding investigational medicinal products other than placebo, the sponsor shall submit annually through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational medicinal product used in a clinical trial for which it is the sponsor.

2.   In the case of a clinical trial involving the use of more than one investigational medicinal product, the sponsor may, if provided for in the protocol, submit a single safety report on all investigational medicinal products used in that clinical trial.

3.   The annual report referred to in paragraph 1 shall only contain aggregate and anonymized data.

4.   The obligation referred to in paragraph 1 starts with the first authorization of a clinical trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor with the investigational medicinal product….”.

Please also see Article 53, Spanish RD 1090/2015:

“1. The sponsors of clinical trials will prepare an annual safety report in which the safety of the investigational medicinal product is evaluated, taking into account all the available information. Said report will be communicated to the Spanish Agency for Medicines and Medical Devices and to the CEIm.

2. Regardless of the annual safety report, the sponsor will prepare an "ad hoc" assessment report whenever there is a relevant safety problem. This report will be submitted immediately to the Spanish Agency for Medicines and Medical Devices and to the CEIm as indicated in the previous section.

3. The presentation of the annual safety report and other safety reports by the sponsor will comply, in any case, with the criteria and the procedure specified in articles 43, 45, and 53 of Regulation (EU) No. 536/ 2014 of the European Parliament and of the Council, of April 16, 2014. 

4. Sponsors of clinical trials in which investigational medicinal products, excluding placebos, are authorized and, according to the clinical trial protocol, are used in accordance with the terms of the marketing authorization may submit a simplified report in accordance with the instructions for conducting clinical trials in Spain published by the Spanish Agency for Medicines and Medical Devices.”

2.17 Do the country regulations allow a Decentralized Clinical Trial (DCT) model (e.g., eICF, ePROs administration, remote investigator site, etc.)?

Yes.

Reference to DCT requirements can be found within section 13 of the Instruction Document of the AEMPS for conducting clinical trials in Spain.

“In December 2022, the European Commission (EC), the Heads of Medicines Agencies (HMA), and the European Medicines Agency (EMA) released a “Recommendation paper on decentralized elements in clinical trials” that aims to facilitate the conduct of decentralized clinical trials (DCTs) while safeguarding the rights and well-being of participants as well as the robustness and reliability of the data collected.

The aim of DCTs is to make it easier for patients to participate in clinical trials by reducing the need to travel to central trial sites. This approach has the potential to make clinical trials available to a wider demographic of participants and reduce drop-out rates.

This paper addresses general principles in the conduct of clinical trials with decentralized elements, including the roles and responsibilities of the sponsor and investigator, remote informed consent process and electronic signature, delivery of IMP to the trial participant, procedures at home, data management, and trial monitoring. In addition, an overview of the current national provisions per EU member state is outlined in an appendix to the paper. 

A summary of the decentralized elements planned in the clinical trial should be provided in the cover letter of the clinical trial application. If it is determined that decentralized elements are likely to have a significant impact on scientific validity, data integrity, benefit-risk ratio or impact on the protection of trial participants’ rights, these should be considered in a specific and documented risk-benefit assessment.”

2.18 Has a fully virtual trial (DCT) been conducted in the country yet? If so, please provide an example including the registration number and any link to it, whether COVID/non-COVID trials.

Yes, at least one clinical trial has been approved with a fully decentralized arm and is currently recruiting in Spain, this study can be found on the CTIS portal with reference number 2022-500449-26-00 organized by Trials@Home.

2.19 Are there any non-regulatory DCT initiatives in the country, such as where investigator sites and local CROs founded an alliance?

Yes, Farmaindustria has been advocating the implementation of DCTs within the clinical investigation in Spain.

2.20 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol?

Yes. Relevant provisions of the local regulation, i.e. Spanish RD 1090/2015 are provided as below:

“Art. 29. Communication of serious breaches.

1. Serious breaches of the authorized protocol or of this royal decree that have occurred in Spain must be communicated by the sponsor, without undue delay and no later than 7 calendar days from the date on which the breach was learned, to the Spanish Agency for Medicines and Medical Devices and the CEIm by the means indicated in article 21.

2. For these purposes, a serious non-compliance will be understood as one that can significantly compromise the safety and rights of the test subjects or the reliability and solidity of the data obtained in the clinical trial.

3. The Spanish Agency for Medicines and Medical Devices will inform the health authorities of the autonomous communities of those serious breaches that directly affect centers that belong to their community.”

“Art. 39.3(e):

The sponsor's responsibilities are to request the opinion of the CEIm and the authorization of the Spanish Agency for Medicines and Medical Devices, as well as notify them of the start of the trial, serious breaches of the protocol, and other necessary information, obtaining the appropriate authorizations, without prejudice to the communications that they must carry out to the autonomous communities, in accordance with article 19.”

Art. 41.2(f)

“The investigator’s responsibilities are to immediately notify the sponsor of serious breaches of the protocol.”

Articles 44 & 45 also deal with provisions on inspection by AEMPS of compliance with the GCP and the applicable legislation through which any serious breach can be reported. 

2.21 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

Yes, the sponsor is deemed liable for such matters and is required to have insurance in place before the commencement of the trial.

Please see the relevant provision of Spanish RD 1090/2015 below:

“Art. 9. Compensation for damages.

1. In clinical trials other than "low-level intervention clinical trials" the sponsor will ensure that the trial subject is compensated for any damages suffered as a result of the trial. This compensation will be independent of the financial capacity of the sponsor, the researcher, and the center.

2. The sponsor of the trial is responsible for having contracted an insurance or financial guarantee that covers the damages and losses indicated in section 1, at the same time as the responsibilities that the sponsor, the principal investigator, and their collaborators could incur. , including the contracted clinical researchers, and the hospital or center where the clinical trial is carried out, which must be documented prior to carrying out the trial, except in the case of "low-level intervention clinical trials".

3. In the case of clinical trials falling within the definition of "non-commercial clinical research", an application may be submitted without having contracted the insurance or financial guarantee referred to in section 2. However, if favorable the opinion of the CEIm, the authorization resolution will be subject to the presentation of said documentation to the CEIm itself within a period of thirty calendar days, and the study may not begin until it considers that the required insurance or financial guarantee is in place.

4. Damages to the study subject that could result as a result of a low-level intervention clinical trial will not need to be covered by an insurance contract or financial guarantee referred to in section 2 if they were covered. by individual or collective professional civil liability insurance or equivalent financial guarantee from the health center where the clinical trial is carried out.

5. When the sponsor and principal investigator are the same person and the clinical trial is carried out in a health center dependent on a public administration, the latter may adopt the measures it deems appropriate to facilitate the guarantee of the specific risks derived from the trial under the terms indicated in the previous sections, in order to promote research.

6. The actions of the "contracted clinical researchers" referring to that medical assistance to the subject that, concurring in time with the development of the trial, is carried out for reasons unrelated to it or does not bring cause of it, must be covered by an insurance like the one that covers the rest of the staff of the center for the aspects not covered by the insurance of the clinical trial.”

Art. 10. Liability regime.

1. It is presumed, unless proven otherwise, that the damages that affect the health of the trial subject during the trial and in the year following completion of the treatment have occurred as a result of the trial. However, once the year is over, the subject of the trial is obliged to prove the link between the trial and the damage caused.

2. For the purposes of the liability regime provided for in this article, all expenses derived from the impairment in the health or physical condition of the person subjected to the clinical trial will be subject to compensation, as well as the economic damages that derive directly from said impairment. , as long as this is not inherent to the pathology under study or to the evolution of the disease as a consequence of the ineffectiveness of the treatment.

3. The minimum amount that will be guaranteed as liability will be 250,000 euros per person undergoing a clinical trial and may be received in the form of flat-rate compensation or income equivalent to the same capital. A maximum insured capital or maximum amount of the financial guarantee per clinical trial and annual payment of 2,500,000 euros may be established.”

In addition, the Instruction Document of the AEMPS for conducting clinical trials in Spain lists a couple of templates, those are:

• Annex VA. Insurance Certificate Model
• Annex VB. Additional responsibility commitment in relation to coverage of clinical trial insurance.

*Links to the English templates published by the AEMPS tend to fail. Please refer to the main page where the English templates can be found  - “Annexes to Instruction document for conducting clinical trials in Spain.”