Scope of this category for Spain:
According to article 2 of Royal Decree 1090/2015, in Spain Clinical Research involving human subjects includes different types of studies:
"Clinical study": Any research in relation to humans intended:
- To discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products.
- To identify any adverse reaction to one or more medicinal products.
- To study the absorption, distribution, metabolism and excretion of one or more medicinal products, with the objective of ascertaining the safety and/or efficacy of said medicinal products.
"Clinical trial": A clinical study which fulfils any of the following conditions:
- The assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned.
- The decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study.
- Diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.
"Low-intervention clinical trial": A clinical trial which fulfils all of the following conditions:
- The investigational medicinal products, excluding placebos, are authorised.
- According to the protocol of the clinical trial:
- The investigational medicinal products are used in accordance with the terms of the marketing authorisation; or
- The use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned.
- The additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any Member State concerned.
Non-Interventional Studies:
In Spain, non-interventional trials are called observational studies as defined in Article 58 of Decree No. 1/2015. This refers to a study in which medicinal products are prescribed in the usual manner, according to the conditions outlined in the authorization. The allocation of a patient to a particular therapeutic strategy will not be decided in advance by a trial protocol but will be determined by standard medical practice. The decision to prescribe a particular medicinal product should be clearly separated from the decision to enroll the patient in the study. No intervention, whether diagnostic or follow-up, other than standard clinical practice, will be applied to patients. Epidemiological methods will be used for the analysis of the data collected.
Competent Authority
Contact Details
N/A
Trial Authorisation / Registration / Notification
The Spanish Agency of Medicines and Medical Devices shall maintain a registry of clinical studies with medicinal products for human use on its website.
The (REec) Spanish Clinical Studies Registry shall include the following information:
a) Compulsorily, clinical trials with medicinal products for human use that are authorised by the Spanish Agency of Medicines and Medical Devices, in accordance with this Royal Decree.
b) Compulsorily, non-interventional post-authorisation studies that are to be conducted and have been classified by the Spanish Agency of Medicines and Medical Devices.
c) Voluntarily, as with 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 including cases, or although not including cases, that have a Spanish contribution
considered as significant.
There is no general national healthy volunteer registry.
Royal Decree (RD) 1090/2015 see article 47 and 48
Observational studies:
All studies have to be approved by EC. Depending on the type of study, they will also have to be approved by local/national CA. Please refer to: see: Orden SAS/3470/2009)
In case of doubt regarding the classification of the study, please send an email to: farmacoepi@agemed.es, requesting AEMPS to provide a classification.
Registries: for further information on registries with IMPs and MD, please refer to:
http://www.aemps.gob.es/informa/notasInformativas/laAEMPS/2013/NI-MUH_07-2013-reec.htm
Submission of Application
The required application documentation is provided in Royal Decree (RD) 1090/2015.
Submission Format
The AEMPS website (Section Clinical Trials) provides practical guidance and manuals on the use of the portal ECM and the application modality.
Link for submission: http://www.aemps.gob.es/ (click in “sede electrónica”, to upload the xml file with the protocol)
Related information to the application procedure is described in Royal Decree 1090/2015 (Chapter 5, section 2, Article 21).
Language of Submission
Royal decree 1090/2015
Submission Fees
(1) A first clinical trial with MPs that are not authorised in a country that belongs to the International Conference on Harmonisation (ICH) with active substances or combinations of active substances that are not authorised in Spain:
Fee: €4327.26
(2) a) A clinical trial with a MP that is authorised in a country other than Spain (belonging to the ICH).
b) Clinical trials with medicines that are not authorised in any country belonging to the ICH, following a first clinical trial included in the category (1)
c) Clinical trials with the characteristics outlined (1) in the event of resubmission when the outcome of the first application was a withdrawal of the application or was refused
d) Clinical trials with a medicine that is not authorised in a country belonging to the ICH with active substances that are authorised in Spain.
Fee: € 412.12
3) a) Clinical trials with MP authorised in Spain, irrespective of their specific labelling for the trial.
b) Clinical trials whose sponsor is a researcher or group of researchers and in which a Pharmacy Service is responsible for preparing or blinding the medicines under investigation
Fee: € 114.55
(4) Procedure for classifying a veterinary medicine that is not authorised in Spain as investigational medicinal product. Fee: € 283.76
5) Fee for the veterinary clinical trials procedure. Fee: € 114.55
The current fees and payment modalities are provided on the AEMPS website: Medicines for human use>Clinical research with medicines > Tasas/Fees
Timelines Authorisation
The CA has 10 days to validate the application documentation and to notify the applicant on the decision.
In case of any formal deficiencies communicated by the CA, the sponsor has 10 days to correct them. (Art 5. Regulation (UE) n.º 536/2014)
NB! CA authorization is only possible provided that the EC’s favourable opinion has been issued before the deadline.
There is NO clock stop if further information or clarification is requested from sponsor (as opposed to REC assessment).
Considering this, it is advisable that the CTA is submitted to the EC(s) at least 2.3 weeks prior to the date of submission to the CA!
Amendments/Substantial Amendments
The standard application form to be used for the submission of substantial amendments is provided on the AEMPS website in section: Aclaraciones sobre la aplicación de la normativa de ensayos clínicos:
Anexo 1C: "Solicitud de autorización de una modificación relevante a un ensayo clínico con medicamentos de uso humano a la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) y de dictamen por el Comité Ético de Investigación Clínica (CEIC)."
The application must be in writing, dated and signed by the sponsor and investigator.
NB: In case of amendments to clinical trials with gene therapy, somatic cell therapy, or GMO medicinal products, the time span can be extended and will be communicated to the sponsor.
End of trial
In case of premature trial termination, the notification must include the study data obtained until the study termination as well as the reasons for this and the measures taken relating to the study participants.
Additionally the promotor will send to the CA a copy of the summary of the Clinical Trial results. This information will be sent (maximum timeframe) after 1 year of the anticipated trial ending.
Ethics Committee
Contact Details
117 Ethics Committees (EC) in Spain
Ethical Review - General
According to thIS Decree, only the accredited ethics committees as CEIms - Committees on Ethics of Research with Medicines - are authorized to evaluate the clinical trials with medicinal or healthcare products.
Submission to the EC and CA can be done in any order or simultaneously (depending on the Sponsor’s preference).
NB! CA authorization is only possible provided that the EC’s favourable opinion has been issued before the deadline.
The Sponsor can select the EC for the evaluation for the CT. There will be only one EC that will do a unique CT evaluation.
Submission of Application
The documentation can be submitted at any time
Submission Format
Further practical information is provided by the AEMPS (see: AEMPS - Clinical Trials) or on the MSSSI website in section Pharmacy > Clinical Research Ethics Committee Co-ordination Centre
Language of Submission
Submission Fees
Most of the RECs charge fees for reviewing the protocol and the assessment of the CT applications. The fees vary between the different RECs.
Fees are provided on the corresponding EC website or requested by phone (contacts are provided on the MSSSI website in section Directorios de los CEIC's acreditados en España).
Timelines Ethical Review
Amendments/Substantial Amendments
A. Submission without corrections neither clarifications: 10 days for validation + 45 days for evaluation + 5 days of final response.
B. Submission with corrections: 10 days for validation + 11 days for corrections + 45 days of evaluation + 5 days of final response.
C. Submission with clarifications: 10 days of validation + 45 days of evaluation + 31 days for responding of objections (clarifications) + 5 days of final response.
D. Submission with corrections and clarifications: 10 days of validation + 11 days of corrections + 45 days of evaluation + 31 days for responding of objections (clarifications) + 5 days of final response.
Close
End of study
Study Specific Requirement
Sponsor
Study participants - informed consent
The provisions related to the informed consent form and the patient information sheet is provided in Royal Decree 1090/2015 art 4 and Regulation (UE) n.º 536/2014.
Informed consent obtained from vulnerable subjects (e.g. minors and incapacitated adults) who are potentially involved in the CT is specifically covered in Art 4 of Royal Decree 1090/2015.
Study participants - vulnerable population
LEGAL AGE OF CONSENT:
18 years
MANDATORY / SUGGESTED AGE RANGES DEFINED FOR ASSENT:
0-11 years
12-17 years with own signature
NUMBER OF REQUIRED SIGNATORIES:
One parent
OFFICIAL LANGUAGE OF INFORMED CONSENT:
Spanish
INFORMATION ON MATERIAL USED TO DESCRIBE THE CLINICAL TRIAL TO THE MINOR:
The child must also receive information adapted to their age and mental maturity according to the European regulation.
ADDITIONAL INFORMATION (INCLUDING REFERENCE FOR TEMPLATE):
• Prior informed consent of the parents who hold custody or of the legal representative of the minor must be obtained, and the minor, if under 12 years of age, must be heard if the minor has sufficient judgment. The informed consent form of the parents shall be valid provided it is signed by one of them with the express or tacit consent of the other, which should be adequately documented, as stipulated in article 156 of the Civil Code. When the subject's condition allows, or in any case when the minor is twelve years of age or older, the subject must also give his/her consent to participate in the trial.
• Reference legislation:
o Royal Decree 1090/2015 (Real Decreto 1090/2015, de 4 de diciembre, por el que se regulan los ensayos clínicos con medicamentos, los Comités de Ética de la Investigación con medicamentos y el Registro Español de Estudios Clínicos)
o Law 29/2006 on Medicinal Products and MD
o Law 14/2007 (Ley 14/2007, de 3 de julio, de Investigación biomédica - in Title V Chapters I-IV)
o Royal Decree 1716/2011 (Real Decreto 1716/2011, de 18 de noviembre)
• IC template(s) / guidelines / information sources:
o The Agencia Española de Medicamentos y Productos Sanitarios (AEMPS); A state agency within the Spanish Ministry of Health, Social Services and Equality -> Medicines for Human use - > Clinical Research with Medicines
o The Ministry of Health, section about regulation of clinical trials:
o Royal Decree 1090/2015, of 4 December, regulating clinical trials with medicinal products, Ethics Committees for Investigation with medicinal products and the Spanish Clinical Studies Registry (English version)
SOURCE(S):
http://www.aemps.gob.es/en/investigacionClinica/medicamentos/home.htm
http://www.aemps.gob.es/en/legislacion/espana/investigacionClinica/ensayos.htm
https://www.aemps.gob.es/legislacion/espana/investigacionClinica/docs/Royal-Decree-1090-2015_4-December.pdf
Study participants - compensation & reimbursement
Compensations are compulsory when there is no direct clinical benefit for the patient. Otherwise, compensations are not mandatory and are only paid to compensate for expenses (e.g. transport tickets) or potential inconveniences (like extra visits)
(see Art 3 and 32 of Royal Decree 1090/2015)
Study participants - recriutment & trial outcome
The sponsor is obligated to publish the study results, regardless of positive or negative outcome and to inform the patients on the outcome of the clinical trial according to Art 1 of Royal Decree 1090/2015.
Data protection
The protection of the data of study subjects is mentioned in Art 1-10 of Royal Decree 1090/2015 and safeguarded by Ley Orgánica 15/1999, de 13 de diciembre, de Protección de Datos de Carácter Personal.
Insurance
The required compensation sum is: • Minimum 250000 € per patient as flat sum or 25000 € per patient/year) • Maximum 2500000 € for the whole study/ year
Quality insurance, quality control
Royal Decree 1090/2015
Archiving & data management
National Legislations
General Information
Agencia Estatal Boletín Oficial del Estado (BOE- State Agency Official State Gazette).
Legal framework for clinical trials with medicinal products
- Royal Decree 1090/2015, of 4 December, regulating clinical trials with medicinal products : Real Decreto Legislativo 1/2015, de 24 de julio, por el que se aprueba el texto refundido de la Ley de garantías y uso racional de los medicamentos y productos sanitarios. (BOE núm. 177, de 25 de julio de 2015).
Available at (only in Spanish) : https://www.aemps.gob.es/en/legislacion/espana/laAEMPS/general.htm#leyes
- Corrección de errores del Real Decreto Legislativo 1/2015, de 24 de julio, por el que se aprueba el texto refundido de la Ley de garantías y uso racional de los medicamentos y productos sanitarios. (BOE núm. 306, de 23 de diciembre de 2015).
Available at (only in Spanish) : https://www.aemps.gob.es/en/legislacion/espana/laAEMPS/general.htm#leyes
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Background
The Royal Decree Royal Decree 1090/2015 aims to adapt the Spanish legislation to the future application of the Clinical trials - Regulation EU No 536/2014 of 16 April 2014. Also, it aims to cover those aspects that are subject to national adaptations as well as any others aspects requiring clarification ( for instance, the decree provides a definition of "non commercial trials". See definitions)
This Royal Decree entered into force in January, 2016, except for a few paragraphs, which shall enter into force on the date on which the Regulation (EU) No. 536/2014 will enter into application.
Pending the application of the aforementioned EU Clinical trial regulation (no sooner that 2019) and the development of a fully functional EU clinical trials portal and database, the Spanish Royal Decree has established the following transational procedure :
- transitional procedure for authorization of a clinical trial before full functionality of the EU portal and the EU database
- transitional arrangements relating to the functions of evaluation of the ethics committee (currently called "CEICs") ( for instance, according to the Decree, only the accredited ethics committees as CEIms - Committees on Ethics of Research with Medicines - will be able to evaluate the clinical trials with medicinal or healthcare products).
Blood & Tissue Samples
Regarding clinical trials with cells tissues, considered as medicinal products, all legislation related to clinical trials with medicinal products applies.
Other applicable legislation:
• Royal decree 65/2006, regulating the import ad export process of biological samples.
• Royal decree 1301/2006, regulating the donation, management and therapeutic use of human cells and tissues (not considered as medicinal products)
• Law 14/2007 (Ley 14/2007 de Investigación Biomédica): regulates Biomedical Research and biological samples.
• Royal decree 178/2004 lays down the legal principles of the contained use, release and marketing of genetically modified organisms (GMO).
• Royal decree 664/1997 deals with the exposure to biological agents (including cell cultures used to amplify the gene therapy vectors).
Data protection
Ley Orgánica 15/1999, de 13 de diciembre, de Protección de Datos de Carácter Personal.
Definitions
IMP/IMP Study
The Spanish definition for IMP (Royal Decree 1090/2015, Chapter 1, article 2, letter I) is the literal translation of the European IMP definition provided in REGULATION (EU) No 536/2014
OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014.