Clinical research with medicines is the basic element that allows medicines to be authorised by the medicines agencies, which are marketed by their holders with the guarantees that the legislation and finally arrive at the clinical practice for the benefit of the patients. It also allows research into new forms of use or more efficient forms of use once the drugs are already marketed. In short, clinical research allows to generate high quality knowledge to develop therapeutic tools that improve the ones already available and contribute to the prevention, relief and cure of diseases and improvement of the quality of life of the population.

To do this, clinical research should be developed in an environment that ensures the protection of people who participate in it and in line with elements such as the Declaration of Helsinki, approved by the Medical Association. World, and the Council of Europe Convention for the Protection of Human Rights and the Dignity of the Human with respect to the applications of biology and medicine, signed in Oviedo. It must also guarantee the basic principles set out in Law 41/2002 of 14 November, basic regulation of patient autonomy and rights and obligations regarding information and clinical documentation, and Law 26/2011, 1 of August, to adapt regulations to the International Convention on the Rights of Persons with Disabilities. Finally, it must also ensure that the results obtained from it are of a quality and useful for the purposes set out above, and should therefore be developed in a context of maximum transparency.

At the same time, it is necessary to encourage the clinical investigation of orphan drugs and medicines intended for the treatment of population groups such as children, women and elderly people who have traditionally been poor. represented in clinical research.

European harmonisation in the field of clinical trials is due both to the general rules on medicinal products and specifically to Directive 2001 /20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States on the application of good clinical practice in the conduct of clinical trials on medicinal products for human use. In Spain, the Royal Decree 223/2004 of 6 February, which regulates clinical trials with medicinal products, came to incorporate this directive in its entirety into the internal legal order, laying down the basic principles and requirements that have regulated until today the conduct of clinical trials with drugs and the Ethical Committees of Clinical Research as guarantors of their ethical and scientific quality. Subsequently, Law 29/2006, of July 26, of guarantees and rational use of medicines and medical devices, as at present the recast text approved by the Royal Legislative Decree 1/2015, of July 24, amparo in its title III clinical trials with medicinal products under the heading "Of the guarantees of research on medicinal products for human use" and, in addition, Order SCO/256/2007 of 5 February laying down principles and guidelines detailed clinical good practice and the requirements for authorising the manufacture or import of Medicinal products for human use research have incorporated in their entirety into national law the Commission Directive 2005 /28/EC of 8 April laying down the principles and detailed guidelines for good practice clinical trials on medicinal products for human use, as well as the requirements for authorising the manufacture or import of such products.

However, the regulation of clinical trials with medicinal products has been the subject of some public criticism and analysis in recent years that have focused on the complexity of the trial authorisation procedure, which It imposed a disproportionate bureaucratic burden on the authorisation which has hindered clinical research in the European Union. Although the European Commission published different documents to further improve and harmonise the implementation of the legislation, Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on the clinical trials of medicinal products for human use, and repealing Directive 2001 /20/EC and in which profound changes are being made in order to simplify procedures without subtracting guarantees for the participants in the trials clinical.

The new Regulation sets out, on the one hand, common procedures for the authorisation of clinical trials across Europe, urging Member States to cooperate in the assessment through a single and common position, but leaves outside this cooperation, on the other hand, those aspects of an intrinsically national nature which require an assessment by each Member State. In addition, in order to promote clinical research in the European Union, it sets very high assessment deadlines, maintains the concept of tacit authorisation and does not set minimum time limits for authorisation.

The new European regulation also introduces some changes in definitions that are of great relevance, especially but not only for research promoted by academic researchers. Thus, it introduces the concept of "low-level clinical trial" on which it calls to adopt less rigorous standards in aspects such as monitoring, content of the master file or traceability, without prejudice to the safety of the individuals who participate in them.

In short, and when the European Commission is opting for the legal formula for regulation, the aspects regulated in this regulation are of direct application to the Member States and will result in less variability in the application of the rules. rules. However, the regulation itself leaves to national development basic aspects such as the organization by which each State reaches the unique position in the evaluation, the evaluation of the ethical aspects and the informed consent or, among others, the mechanisms for compensation. On the other hand, since the date of application of the Regulation is postponed until no later than May 2016, maintaining the possibility for the sponsor to request the authorisation of a clinical trial under the protection of Parliament Directive 2001 /20/EC At least in the three years following the date of publication of the Regulation, some aspects of the transposition of the Directive should be temporarily maintained within three years of the date of publication of the Regulation.

The changes adopted in Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, therefore require the introduction of substantial amendments to national legislation with the the purpose of ensuring compliance with the Regulation is applicable. However, after ten years of the entry into force of Royal Decree 223/2004 of 6 February, there were also some possible improvements to be made in the procedure for the authorisation of clinical trials in Spain. These, in line with those of the new regulation, cover aspects such as increased efficiency in the process of communication and evaluation or the delimitation of the responsibilities of all the actors involved. All this has made it advisable not to wait until the date of application of the regulation to take those necessary changes in national legislation with the aim of adapting quickly to the new regulation and maintaining a competitive position of Spain in the European and global context of clinical research.

In this regard, there are two aspects of national development of legislation that deserve a separate comment. On the one hand, it was necessary to undertake the integration of the Ethical Committees of Clinical Research into the development of Law 14/2007, of July 3, of biomedical research. This law determines in its third transitional provision that the Ethical Committees of Clinical Research will cease to exist at the time the Research Ethics Committees are constituted. In the development of Law 14/2007, of July 3, the creation of a National Authority of Ethics Committees of the Research that takes care of the general aspects of coordination and the registration of the Committees is also foreseen. However, given the peculiarities of clinical research with medicinal products and the needs imposed in the new regulation, the coordination of the single decision for clinical trials with medicinal products, as well as other aspects of According to this royal decree, supervision concerning those Committees of Research Ethics accredited for the evaluation of drug studies will correspond to the Spanish Agency for Medicines and Health Products. In addition, the additional requirements to be met by the Research Ethics Committees in order to be accredited as Ethics Committees for research with medicinal products, taking into account the specificities applicable to the research, are established. clinical research with medicinal products and medical devices, and taking as a reference the accreditation criteria to be determined in the development of the said law.

Finally, this royal decree develops an aspect of the recast text of the Law on the guarantees and rational use of medicines and medical devices, which, in its article 62, lays the foundations of the public and free national registry clinical trials with medicinal products for human use as a necessary measure for transparency. To this end, the Spanish Agency for Medicines and Health Products should make available to the public on its website certain information on the clinical trials authorised. In this royal decree, the Spanish Registry of Clinical Studies is developed, from a broader perspective, to allow the recording of observational studies with drugs that are classified by the Agency. Spanish of Medicines and Sanitary Products. In addition, the creation of this register has taken into account the public utility that is raised in the recast text of the Law on guarantees and the rational use of medicines and medical devices, for clinical trials with medicinal products. by extending it, on a voluntary basis, to all prospective clinical studies outside the field of medicinal products. Thus, registration will be compulsory and complete in terms of clinical studies with medicinal products, but it is open to use as a voluntary registration for any other type of clinical study when its promoters wish to use it with the aims set out in the International Records Platform of Clinical Trials of the World Health Organization.

For the World Health Organization, the registration, publication and access of the public to the relevant content of clinical trials is a scientific, ethical and moral responsibility. The World Health Organization itself has established what is the minimum set of data from a clinical trial that should be made public. This standard is the same as that adopted by the European Parliament and the Council in order to make public the data contained in the EudraCT database containing information from clinical trials with medicinal products in which a centre is involved. located in the European Economic Area and which have been authorised by the competent national authority. The content of the Spanish Register of Clinical Studies is in line with the standards set on the international platform of clinical trial records of the World Health Organization. It has also been taken into account that the applicant for a clinical trial authorisation with medicinal products or classification for observational studies already provides the information on the clinical study with medicinal products to the Spanish Agency Medicines and Health Products in accordance with the Spanish and European regulations in this respect. Therefore, information and communication technologies will be used to speed up processing.

This royal decree therefore seeks to adapt Spanish legislation to make the current and future application of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 viable and to develop those aspects that the regulation leaves to national legislation. This aims to promote and facilitate clinical research with medicines in Spain, knowledge generation, transparency, the safety of participants and the usefulness of results. In short, consolidate the trust of the society in the research and favor its progress.

In accordance with the provisions of Article 149.1.16 of the Constitution, this royal decree is dictated in accordance with the exclusive competence of the State in matters of legislation on pharmaceutical products, ensuring, as regards the processing of personal data, compliance with the Organic Law 15/1999 of 13 December on the Protection of Personal Data and its implementing rules.

According to the provisions of Law 16/2003, of 28 May, of the cohesion and quality of the National Health System, this royal decree has been the subject of prior report by the Advisory Committee and the Council's Plenary Session. Interterritorial of the National Health System. In addition, the Spanish Data Protection Agency has issued its mandatory report, pursuant to the provisions of Law 15/1999 of 13 December, and the Statute of the Agency, approved by Royal Decree 428/1993, of 26 of March.

In the process of drawing up this standard, the autonomous communities, the cities of Ceuta and Melilla, and the affected sectors have been consulted among others.

In its virtue, on the proposal of the Minister of Health, Social Services and Equality, with the prior approval of the Minister of Finance and Public Administrations, in agreement with the Council of State and after deliberation of the Council of Ministers, at their meeting on 4 December 2015,

DISPONGO:

CHAPTER I

General provisions

Article 1. Object.

1. This royal decree will apply to clinical trials with medicinal products for human use that are carried out in Spain and aims to:

(a) Develop the specific provisions for the application in Spain of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials for medicinal products for human use, and Directive 2001 /20/EC on clinical trials with medicinal products for human use in Spain is repealed.

b) Regular Research Ethics Committees with medicines, as well as the Spanish Registry of Clinical Studies, which is made up of both clinical trials and the post-authorisation studies that are carried out with medicinal products for human use.

For these purposes, the administration of an investigational medicinal product to individual patients, in the field of medical practice and with the sole fundamental purpose of medical practice, will not be considered a clinical trial with medicinal products. achieve a therapeutic benefit for the patient. In this case, the use of unauthorised medicinal products or under conditions of use other than those authorised shall be governed by the provisions of Royal Decree 1015/2009 of 19 June, which regulates the availability of medicinal products in situations special.

2. The medical practice and professional freedom of prescription of the doctor or other health professionals shall in no case be covered by the conduct of unauthorised clinical trials or the use of secret or undeclared remedies to the authority. health.

Article 2. Definitions.

1. For the purposes of the provisions of this royal decree, it is understood by:

(a) "Human use medicinal product" means any substance or combination of substances which is present as a property holder for the treatment or prevention of diseases in humans or which can be used in humans or be administered to humans in order to restore, correct or modify physiological functions by exercising pharmacological, immunological or metabolic action or to establish a medical diagnosis.

(b) "Radiopharmaceutical" means any product which, when prepared for use for therapeutic or diagnostic purposes, contains one or more radionuclides (radioactive isotopes).

c) "Adverse reaction": Any harmful and unintended response to a drug.

d) "Serious adverse reaction": Any adverse reaction that causes death, may be life-threatening, requires hospitalization of the patient, or prolongation of the existing hospitalization, causes a disability or Significant or persistent disability, or a birth defect or birth defect. For the purposes of their notification, serious suspected adverse reactions which are considered to be important from the medical point of view, even if they do not meet the above criteria, such as those at risk to the patient or require an intervention to prevent any of the previous outcomes and all suspicions of transmission of an infectious agent through a drug.

e) "Primary conditioning": The packaging or any other form of packaging that is in direct contact with the medicinal product.

f) "Outer packaging": The packaging in which the primary packaging is located.

(g) "Health product" means any instrument, device, equipment, software, material or other article, used alone or in combination, including software intended by its manufacturer for purposes specific diagnosis and/or therapy and which are involved in their proper functioning, intended by the manufacturer to be used in human beings for the purpose of:

1. Diagnosis, prevention, control, treatment, or relief of a disease.

2. º Diagnosis, control, treatment, relief, or compensation for an injury or deficiency.

3. Research, replacement or modification of the anatomy or a physiological process.

4. Regulation of conception, and which does not exercise the main action to be obtained inside or on the surface of the human body by pharmacological, immunological, or metabolic means, but whose function they may be contribute such means.

h) "Clinical study": All research on persons intended for:

1. Uncover or check the clinical, pharmacological or other pharmacodynamic effects of one or more medications.

2. Identify any adverse reactions to one or more medications.

3. Study the absorption, distribution, metabolism, and excretion of one or more medications, with the aim of determining the safety and/or efficacy of such medications.

i) "Clinical trial": A clinical study that meets any of the following conditions:

1. The test subject is assigned in advance to a given therapeutic strategy, which is not part of the usual clinical practice of the Member State involved.

2. The decision to prescribe investigational drugs is taken together with the decision to include the subject in the clinical study.

3. º diagnostic or follow-up procedures are applied to test subjects that go beyond the usual clinical practice.

j) "Low-level clinical trial": A clinical trial that meets all of the following conditions:

1. The investigational drugs, excluding placebos, are authorized.

2. º According to the clinical trial protocol:

1. The investigational drugs are used in accordance with the terms of the marketing authorization, or

2. The use of investigational medicinal products is based on evidence and is supported by published scientific data on the safety and efficacy of such investigational medicinal products in one of the Member States. involved.

3. The complementary diagnostic or follow-up procedures involve an additional risk or burden for the safety of the subjects that is minimal compared to that of the usual clinical practice in one of the States. members involved.

k) "observational study": A clinical study other than a clinical trial.

l) "investigational drug": The one that is being tested or used as a reference, including as a placebo, in a clinical trial.

m) "Normal clinical practice": the treatment that is usually followed to treat, prevent, or diagnose a disease or health problem.

n) 'Advanced research therapy medicinal product': An investigational medicinal product which responds to the definition of advanced therapy medicinal product in Article 2 (1) (a) of Regulation (EC) No 1394/2007 European and Council Regulation (EC) No 726/2004 of 13 November 2007 on medicinal products for advanced therapy and amending Directive 2001 /83/EC and Regulation (EC) No 726/2004

n) "Auxiliary medicinal product": Medicament used for the needs of a clinical trial as described in the protocol, but not as an investigational medicinal product.

(o) 'authorised research medicinal product' means a medicinal product authorised in accordance with Regulation (EC) No 726/2004, or in any Member State concerned, in accordance with Directive 2001 /83/EC, irrespective of the changes in labelling, which are used as an investigational medicinal product.

(p) "authorised auxiliary medicinal product" means a medicinal product authorised in accordance with Regulation (EC) No 726/2004 or, in any Member State concerned, in accordance with Directive 2001 /83/EC, irrespective of changes label, which is used as an auxiliary medicine.

q) "Member State concerned": Member State in which an application for a clinical trial authorisation or a substantial amendment has been submitted pursuant to Chapters II and III of the Regulation respectively (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

r) "Substantial modification" means any change of any aspect of the clinical trial that is carried out after the notification of the decision referred to in Articles 8, 14, 19, 20 or 23 of Regulation (EU) No 536/2014 The European Parliament and the Council of 16 April 2014, which may have a significant impact on the safety or rights of the test subjects or on the reliability and robustness of the data obtained in the clinical trial.

s) "Promoter": Individual, company, institution or organisation responsible for initiating, managing and organising the funding of a clinical trial.

t) "Investigator": Person in charge of conducting the clinical trial at a clinical trial facility.

u) "Principal Investigator": Investigator responsible for a team of researchers conducting a clinical trial at a clinical trial center.

v) "Test Subject": Person involved in a clinical trial, either as a recipient of the investigational medicinal product or as a control.

w) "Informed Consent": The free and voluntary expression by a clinical trial subject of his/her willingness to participate in a given clinical trial, having been informed of all aspects of the clinical trial relevant to their decision to participate or, in the case of minor or incapable test subjects, an authorisation or agreement of their legally appointed representatives to include them in the clinical trial.

x) "Protocol": A document describing the objectives, design, methodology, statistical considerations and organization of a clinical trial. The term "protocol" includes successive versions of the protocols and their modifications.

and) "Investigator's Manual": Collection of clinical and non-clinical data on the investigational medicinal product that are relevant to the study of this medicinal product in humans.

z) "Manufacturing": Total or partial manufacturing, as well as division, conditioning, and labeling operations (including masking).

aa) "Start of a clinical trial": First act of selection of a possible subject for a particular clinical trial, unless the protocol otherwise defines it.

ab) "Completion of a clinical trial": Last visit of the last test subject, or a later time as defined by the protocol.

ac) "Early completion of a clinical trial": Premature termination of a clinical trial for any reason before the conditions outlined in the protocol are met.

ad) "Temporary Paralization of a Clinical Trial": Unanticipated interruption in the protocol of the conduct of a clinical trial by the promoter, which intends to resume it.

(ae) "Suspension of a clinical trial": Interrupting the conduct of a clinical trial by a Member State.

af) "Good clinical practice": Detailed set of ethical and scientific quality requirements for design, direction, development, monitoring, audit, recording, analysis and reporting of clinical trials ensure the protection of the rights, safety and well-being of the test subjects, as well as the reliability and robustness of the data obtained in the clinical trial.

ag) "Inspection": Official review by a competent authority of documents, facilities, files, quality assurance systems and any other resources deemed related by the competent authority with the clinical trial and which can be found at the clinical trial site, at the premises of the sponsor or the contract research organisation or in any other establishment which the competent authority considers appropriate inspect.

ah) "Adverse event": Any incident that is detrimental to the health of a test subject to which a medicinal product has been administered, even if it does not necessarily have a causal relationship to it.

ai) "Serious adverse event": Any incident detrimental to health which, at any dose, makes hospitalization or prolongation necessary, causes permanent or significant disability or disability, from place to a congenital anomaly or malformation, endanger life, or cause death.

aj) "Serious and unexpected adverse reaction": Severe adverse reaction whose nature, severity, or outcome is inconsistent with the reference safety information.

ak) "Clinical Study Report": A clinical trial report presented in an easy and prepared search format in accordance with Module 5 of Part I of Annex I to Directive 2001 /83/EC and presented in a request for a marketing authorization.

2. The following definitions shall also apply:

(a) "Research Ethics Committee (hereinafter CEI)": an independent and multidisciplinary body whose main purpose is to ensure the protection of the rights, safety and welfare of the subjects participate in a biomedical research project and provide public assurance in this respect by giving an opinion on the relevant documentation of the research project, taking into account the views of the legal persons, patients, or patients ' organizations.

b) "Committee on Ethics in Research with Medicinal Products (CEIm)": Research Ethics Committee, which is also accredited in accordance with the terms of this royal decree to issue an opinion in a clinical study with medicines and in a clinical investigation with medical devices.

(c) "Co-promoters" shall mean those promoters who jointly conduct a clinical trial and who are subject to the obligations of the sponsor under this royal decree, unless by written contract they establish their respective responsibilities.

d) "Clinical research with medical devices": Any systematic investigation into one or more human subjects in order to assess the safety or performance of a product.

(e) "Clinical research without commercial animus": Research carried out by researchers without the participation of the pharmaceutical or medical products industry that meets all of the following characteristics:

1. The promoter is a university, hospital, public scientific organization, non-profit organization, patient organization, or individual investigator.

2. The ownership of the research data belongs to the promoter from the first moment of the study.

3. No agreements between the promoter and third parties that allow the use of data for regulatory purposes or that generate an industrial property.

4. The design, realization, recruitment, data collection and communication of research results are maintained under the control of the promoter.

5. º By its characteristics, these studies cannot be part of a development program for a marketing authorization for a product.

f) "Coordinator Investigator": Investigator responsible for coordinating the researchers of the participating centers in a multicenter trial.

g) "Contracted Clinical Investigator": A researcher hired by the Center or research entities related to this for the performance of one or more clinical trials, provided that they have the required degree for the development of the functions assigned to you and you can develop them in the care framework of the center.

(h) "Minor": Test subject, which according to Law 41/2002 of 14 November, basic regulation of the autonomy of the patient and of rights and obligations in the field of information and clinical documentation, has not reached the legal age to give your informed consent.

(i) "Monitor" means a trained professional with the necessary clinical and/or scientific training and competence chosen by the promoter, who is responsible for the direct follow-up of the test. It serves as a link between the promoter and the principal investigator, when they do not participate in the same person. In no case should the monitor be part of the research team.

(j) "Contract Research Organization (hereinafter CRO)": A natural or legal person engaged by the promoter to perform functions or duties of the promoter in relation to the clinical trial.

k) "Person with the modified ability to give consent": Test subject which, for reasons other than those of the legal age to give informed consent, is not able to provide informed consent, according to the national law.

l) "Spanish Register of Clinical Studies": Database, the holder of which is the Spanish Agency for Medicines and Health Products, accessible from its website, free and free for all users, whose objective is to serve as Source of information on clinical studies for citizens.

For the purposes of this Registry, "another type of clinical study" shall be considered as any research that prospectively assigns participants to one or more health-related interventions that are not medicines to study their effects on health indicators.

m) "legal representative of the sponsor" means a person accredited by the sponsor in order to represent him when the sponsor is not established in a Member State of the European Union.

n) "legally appointed representative": a natural or legal person, authority or institution which, in accordance with national law, has the capacity to grant informed consent on behalf of the person with the capacity modified to give your consent or the minor.

n) "Substudy": A study that is part of the clinical trial but may or may not be related to the primary objective of this study, in which a part of the persons included in the clinical trial and/or for which additional informed consent is sought, e.g., pharmacokinetic or pharmacogenetic substudies.

CHAPTER II

Protection of test subjects and informed consent

Article 3. General requirements.

1. A clinical trial subject to this regulation may only be initiated when CEIm and the Spanish Agency for Medicinal Products and Health Products have considered that all of the following conditions are met:

a) The clinical trial is ethically and methodologically correct and is designed to obtain reliable and robust data.

(b) The benefits to the subject of the test or to the expected public health justify the foreseeable risks and disadvantages, and the compliance with this condition is constantly monitored. However, the rights, security, dignity and well-being of the subjects prevail over any other interest.

c) The informed consent of each of the subjects of the trial, freely expressed, is obtained and documented prior to inclusion in the trial in the terms provided for in Articles 4 to 8.

d) The rights of the subject to his physical and mental integrity, and to his privacy, are respected, and the personal data concerning him are protected, in accordance with the Organic Law 15/1999, of December 13, of Protection of Personal Data, and its development regulations, as well as the European regulations in force in this field.

e) The clinical trial has been designed to minimize pain, discomfort, fear and any other foreseeable risk to the test subjects and both the level of risk and the degree of discomfort. specifically defined in the protocol and under constant monitoring.

f) The health care that is dispensed and the medical decisions that are taken on the people are the responsibility of a doctor, a duly qualified dentist or other healthcare professional, always in order to their competencies to provide the necessary care.

g) The test subject has been provided or, if it is not able to give its informed consent, to its legally appointed representative, the contact details of an entity which may provide it with additional information in case of need. In the case of persons with disabilities, this supplementary information shall be provided according to the rules set out in the design principle for all, in such a way as to be accessible and understandable to them.

h) No undue influence, including economic, has been exercised on the subjects of the trial to participate in the trial.

In this regard, persons who participate in trials with a possible direct potential benefit to the research subject or their legal representatives may receive from the sponsor the reimbursement of the extraordinary expenses and loss of productivity resulting from the participation of the person in the test. In special situations, the CEIm may report favourably to the compensation to the test subjects for the inconvenience arising from their participation in the trial, provided that such compensation does not influence the decision of the subject to participate in the study.

The consideration that would have been agreed for the voluntary participation in the clinical trial will be perceived in any case, although it will be reduced proportionally, according to the participation of the subject in the experiment, in the case to decide to revoke their consent and to abandon the trial.

i) The insurance or financial guarantee equivalent to that referred to in Article 9.2 has been contracted, or the coverage provided for in Article 9.4 is available for "low-level clinical trials".

2. Clinical trials should be conducted in accordance with the Helsinki Declaration on ethical principles for medical research in human beings, approved by the General Assembly of the World Medical Association and taking into account the Oviedo Convention for the Protection of Human Rights and the Dignity of the Human with respect to the applications of Biology and Medicine, as well as any other rules that may be applicable.

3. Where the clinical trial provides for the collection of biological samples, the appropriate forecasts shall be drawn up for the purpose of the study to be used for the purposes of Royal Decree 1716/2011 once the test is completed. (a) of 18 November laying down the basic requirements for the authorisation and operation of biobanks for the purposes of biomedical research and for the treatment of biological samples of human origin, and the functioning and organization of the National Register of Biobanks for biomedical research, especially in what is refers to the relevant paragraphs of the informed consent and possible documents for the transfer of biological material.

Article 4. Informed consent.

1. The procurement and content of the informed consent shall follow the provisions of Article 29 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 and Articles 8 and 9 of Law 41/2002 of 14 December 2014. November.

2. When the person who gives the consent is a disabled person, the information will be offered in appropriate formats, according to the rules marked by the design principle for all, in a way that is accessible and understandable, and shall provide the appropriate support measures in order to facilitate the provision of their consent.

3. In the case of minors or persons with the modified capacity and to give their consent, having given the consent of their legally appointed representative, when they reach or recover the ability to consent, their consent must be obtained consent to continue participating in the clinical trial.

4. The person involved in the test shall be notified, particularly in the case of persons with special vulnerability, the access routes to the usual clinical practice for their pathology.

5. The person participating in a clinical trial, by itself or with the assistance of his/her legally appointed representative, or the person linked to it for family reasons or in fact, may revoke his/her consent at any time, without the expression of the cause and without any liability or prejudice arising for the person involved. The withdrawal of the consent shall not affect the activities carried out on the basis of their consent before they have been withdrawn, while ensuring that neither the data nor the samples obtained on the basis of such consent may be used in analysis or studies after the withdrawal date unless consent is obtained to make use of them subsequently or, if the purpose is legitimate, information from sources accessible to the public can be obtained.

6. Where the clinical trial provides for the collection of biological samples, the prospective participant should be informed of what is expected in relation to the future use of the samples. According to Royal Decree 1716/2011 of 18 November, the samples may be destroyed after the end of the test, be incorporated into a collection or an authorised biobank. In the last two cases, the biobank or the person responsible for the collection will be reported, as well as the location where the samples will be guarded.

7. Where a clinical trial is to be carried out exclusively in Spain, without prejudice to the provisions of the foregoing paragraphs and by way of derogation from Article 3 and Articles 5 to 8 of this royal decree, the a researcher obtains the informed consent by means of the simplified means referred to in Article 30 (2) of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, provided that all the conditions laid down in Article 30 (3

.

Article 5. Clinical trials with minors.

1. A clinical trial may only be conducted with minors if, in addition to the conditions laid down in Articles 3 and 4 of this royal decree, all those listed in Article 32 of Regulation (EU) No 536/2014 of the European Parliament and of the European Parliament and of the European Union are fulfilled. of the Council of 16 April 2014.

2. The CEIm that is responsible for evaluating Part II of the report of evaluation of a clinical trial with minors should count among its members with experts in pediatrics or have sought advice on the clinical, ethical and psychosocial issues in the the area of pediatrics.

3. It will be necessary to have obtained the prior informed consent of the parents who are not deprived of the parental authority or of the legal representative of the child, to whom it must be heard if, being under twelve years old, it has sufficient judgment. The informed consent document of the parents shall be valid provided that it is signed by one of them with the express or tacit consent of the other who must be sufficiently documented, as provided for in Article 156 of the Code Civil. Where the conditions of the subject permit and, in any case, where the child is twelve or more years old, he must also give his consent to participate in the trial.

Article 6. Clinical trials with persons with the modified ability to give their consent.

1. A clinical trial may only be conducted in adults who are not in a position to give their informed consent and who have not, and have not refused to give, prior to the commencement of the absence of capacity, where, in addition to the above in 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 are fulfilled.

2. The protocol should be approved by a CEIm which has experts in the disease in question or has sought advice from such experts on clinical, ethical and psychosocial issues in the field of disease and the affected patients.

3. The prior informed consent of the legal representative of the person participating in a clinical trial or the consent of the person linked to it shall be necessary for family reasons or in fact, as appropriate. In any event, the investigator shall reasonably ensure that there are no prior instructions of the person expressed in this respect before submitting a modification of his or her capacity, having to be respected. This eventuality and how to proceed should be provided in the documentation of the test approved by the CEIm.

Article 7. Clinical trials in emergency situations.

1. By way of derogation from Article 3.1.c) and Articles 4 to 6 of this royal decree, where the clinical trial has a specific interest for the population in which the investigation is carried out, and for reasons of need in the administration of the investigational medicinal product, may be subject to a clinical trial without obtaining prior informed consent when all the conditions listed in Article 35 (1) and (2) of the Regulation (EU) are fulfilled. No 536/2014 of the European Parliament and of the Council of 16 April 2014.

2. In this case, whenever circumstances permit, persons linked to it will be consulted in advance for family reasons or in fact.

3. This eventuality and how to proceed should be provided in the documentation of the test approved by the CEIm, and the person, or his/her legally appointed representative, shall be informed as soon as possible and shall give his/her consent to continue in the test, if appropriate, or ratify it in any case.

4. If the test subject or, if applicable, his/her legally appointed representative does not give consent, they shall be informed of their right to object to the use of the data obtained from the clinical trial.

Article 8. Clinical trials with pregnant or breast-feeding women.

Only a clinical trial with pregnant or breast-feeding women may be performed if, in addition to the conditions set out in Articles 3 to 6 of this royal decree, all the conditions listed in the Article 33 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

CHAPTER III

Compensation for damages and liability regime

Article 9. Damages for damages.

1. In clinical trials other than "low-level clinical trials", the sponsor shall ensure that the test subject is compensated for any damages suffered as a result of the test. This allowance shall be independent of the financial capacity of the sponsor, investigator and centre.

2. The sponsor of the test is the person responsible for the contract of insurance or financial guarantee covering the damages referred to in paragraph 1, at the same time as the liabilities incurred by the sponsor, the principal investigator and his/her collaborators, including contracted clinical investigators, and the hospital or centre where the clinical trial is carried out, which must be documented prior to the test, except in the case of "low-level clinical trials".

3. In the case of clinical trials within the definition of "clinical non-commercial research", an application may be submitted without having contracted the insurance or financial guarantee referred to in paragraph 2. If the opinion of the CEIm is favourable, the authorization resolution shall be subject to the submission of the said documentation to the CEIm itself within thirty calendar days. The study may not be initiated until the latter considers that it is it has the required insurance or financial guarantee.

4. Damage to the subject of a study which may result from a clinical trial of low level of intervention shall not be covered by an insurance or financial guarantee contract referred to in paragraph 2. if they are covered by the individual or collective professional civil liability insurance or equivalent financial guarantee of the health centre where the clinical trial is carried out.

5. Where the sponsor and principal investigator are the same person and the clinical trial is carried out in a health care facility dependent on a public administration, the public administration may take the measures it deems appropriate to facilitate the guarantee of the specific risks arising from the test in the terms set out in the preceding paragraphs, in order to encourage research.

6. The actions of the "contracted clinical investigators" referring to the medical assistance to the subject who, in time with the development of the test, is carried out for reasons other than the same or does not bring cause of it, must be covered by insurance such as that which protects the rest of the staff of the centre for the aspects not covered by the clinical trial insurance.

Article 10. Liability regime.

1. It is presumed, unless otherwise proved, that the damage to the health of the subject of the test during its performance and in the year following the completion of the treatment has occurred as a result of the test. However, after the end of the year, the test subject is obliged to test the link between the test and the damage produced.

2. For the purposes of the liability scheme provided for in this Article, all expenditure resulting from the impairment of the health or physical condition of the person subject to the clinical trial shall be liable for compensation, as well as for the economic damage incurred by the person concerned. derive directly from such impairment, provided that it is not inherent in the pathology object of study or the evolution of its disease as a result of the ineffectiveness of the treatment.

3. The minimum amount to be guaranteed as a liability shall be EUR 250,000 per person subject to clinical trial, and may be received in the form of flat-rate or income compensation equivalent to the same capital. A maximum insured capital or maximum amount of the financial guarantee per clinical trial and annuity of 2,500,000 euro may be established.

CHAPTER IV

Drug Research Ethics Committees

Article 11. Supervision and coordination of the Research Ethics Committees with medicinal products.

1. The CEIm will be supervised in the ethical, training and material aspects in the same way as the rest of the Research Ethics Committees (CEI), in accordance with the regulatory regulations of the latter.

2. The Spanish Agency for Medicinal Products and Sanitary Products will facilitate the evaluation procedure and the issuance of the opinion by CEIm in clinical trials with medicinal products to integrate the evaluation of one and the other in a Single decision by clinical trial, valid for the entire State. In order for the integrated assessment to be positive, the evaluation of the Spanish Agency for Medicines and Health Products and the opinion of CEIm should be separately.

3. For the coordination of the opinion in clinical trials with medicinal products, the Spanish Agency for Medicinal Products and Sanitary Products shall develop the following activities:

(a) Facilitate the exchange of information between the Spanish Agency for Medicines and Health Products and CEIm.

b) Coordinate with the autonomous communities, the supervisory bodies of the CIS and the CEIm themselves the development and maintenance of a unique and integrated information system for clinical trials with medicinal products.

c) Manage the clinical trial database with drugs from the CEIm national network.

d) Provide advice to CEIm on procedural issues regarding clinical trials with medicinal products.

e) Any other that, in relation to the activities of the CEIm, is attributed to the current regulations.

Article 12. Functions of the Research Ethics Committees with medicines.

1. In addition to the tasks assigned to them in their capacity as CEI, CEIm shall perform the following tasks in relation to the evaluation of clinical studies with medicinal products or medical devices:

a) Assess the methodological, ethical and legal aspects and issue the relevant opinion.

b) Evaluate the substantial modifications of the authorised clinical studies and issue the relevant opinion.

c) Track the study, from its start to the receipt of the final report.

2. For the performance of these functions in the field of clinical studies with medicinal products, account should be taken of the provisions of Chapter V.

Article 13. Accreditation of the Research Ethics Committees with medicines.

1. In addition to the requirements laid down for the accreditation of the CIS in Law 14/2007, of 3 July, of biomedical research and in its development legislation, CEIm shall comply with the specific accreditation requirements set out in this Regulation. royal decree.

2. The CEIm shall be accredited by the competent health authority in each autonomous community or, in the case of centres dependent on the General Administration of the State, by the competent authority of the State. The Spanish Agency for Medicines and Health Products in coordination with the Autonomous Communities, through the Technical Inspection Committee, will set the common specific criteria for accreditation, inspection and renewal of accreditation. of these committees.

3. This accreditation shall be renewed periodically by the competent health authority, without prejudice to the procedure laid down for the maintenance of its accreditation as a CIS, in accordance with the procedures and time limits to be determined in the Committee. Inspection Technician. Both the initial accreditation and its renewals must be notified to the Spanish Agency for Medicines and Health Products, which will make them public on its website, as well as to those who determine the current regulations of the CIS.

Article 14. Technical Secretariat.

1. Each accredited CEIm must have a professional and stable technical secretariat integrated into the establishment plan of the institution to which it is attached or its supporting institutions.

2. The Technical Secretariat shall have the following functions:

a) Manage the activity of the CEIm.

b) Act as an interlocutor on behalf of CEIm as regards communication with all interested parties, including the Spanish Agency for Medicines and Health Products.

c) Ensure that face-to-face and non-face-to-face meetings are held to ensure that CEIm meets its task at the time.

d) To provide, in collaboration with CEIm members, the reports requested from the Spanish Agency for Medicines and Health Products or any other competent authority to maintain their accreditation as CEIm.

3. The technical secretariat shall have the following means and infrastructure:

a) A leadership performed by a superior entitled with knowledge of medicine, methodology of research, bioethics, pharmacology and regulation of drugs and biomedical research in general.

(b) Specific installations that allow the performance of their work under conditions that guarantee confidentiality. They shall have an appropriate space for the conduct of meetings and for the handling and archiving of confidential documents.

c) Computer equipment with sufficient capacity to handle all the information received and generated by the committee and connection to the information system of the national database of clinical studies with medicinal products and "EU portal" and the "EU database", when available.

(d) An annual specific economic budget, approved by the institution's management, for the training activities to be organised for the members of the CEIm and, where appropriate, the budget allocated to the assistance of its members or potential experts or guests.

Article 15. Composition of the Research Ethics Committees with medicines.

1. The CEIm shall consist of a minimum of ten members, at least one of whom shall be a layman, foreign to biomedical research or clinical care, representing the interests of patients.

Among the members of the aforementioned committee will be physicians, one of whom will be a clinical pharmacologist, a hospital or primary care pharmacist, and a graduate or graduate in nursing.

If in the center there is a Research Commission or an Assistant Ethics Committee, a member of each of them must be part of the CEIm.

At least two members must be foreign to the health professions, one of which must be licensed or graduated in law.

In addition, at least one of its members must be trained in bioethics.

2. The composition of the CEIm should ensure the independence of its decisions, as well as its competence and experience in relation to the methodological, ethical and legal aspects of research, pharmacology and clinical care practice in hospital and extra-hospital medicine.

3. The CEIm shall have a chair, a vice-chair and a technical secretariat, which shall have at the same time the consideration of committee members.

The presidency will hold the committee's representation and its holder will be elected by the vowels in a way that guarantees independence.

The vice presidency will be chosen in a similar manner and will perform the functions of the presidency in the cases of vacancy, absence or illness of the holder.

The head of the technical secretariat shall be the person referred to in Article 14.3.a.).

All members of the committee will have a vote of equal value except for the head of the technical secretariat who will have a voice, but will not vote.

4. The CEIm shall ensure a system of renewal of its members that allows for new additions on a regular basis, while maintaining the experience of the committee.

5. Membership of a CEIm shall be incompatible with any class of interests arising from the manufacture and sale of medicinal products and medical devices. Its members shall ensure the confidentiality of the information to which they have access and shall make a declaration of conflict of interest public.

6. The competent authorities of CEIm shall establish criteria whereby the activities of their members may have a positive impact on their professional career.

Article 16. General rules for the functioning of the Research Ethics Committees with medicinal products.

1. Neither the CEIm as a whole nor any of its members may directly or indirectly receive any remuneration from the sponsor of the study.

2. The collection of fees for the exercise of any of the functions of the CEIm referred to in Article 12 shall be governed by the provisions of Article 33.

The agreement between the centre and the sponsor for the payment of administrative costs will be however possible but should always be regulated as an economic condition more than those provided for in the contract to which the Article 32.1 or be published by the competent, central or autonomic health authority in their respective official bulletins and, in any event, may never be established subject to compliance with any of the functions of the CEIm referred to in Article 12.

3. The CEIm shall draw up and follow for its operation standard working procedures, which shall at least refer to:

a) The composition and requirements that must be met by its members.

b) The periodicity of face-to-face and non-face-to-face meetings, which must at least ensure that the deadlines for evaluating this royal decree are met. CEIm shall make public the calendars of their meetings with information on their availability for the evaluation of new clinical studies in each of them.

c) The procedure to summon its members.

d) Aspects of administrative operation.

e) Cases where a rapid review of the documentation for a clinical study and the procedure to be followed in these cases, including the "low-level clinical trials", can be carried out. intervention ".

f) The initial evaluation of the protocols and monitoring system of the studies.

g) The ordinary and extraordinary decision-making mechanisms that must include a written procedure for decision-making.

h) The preparation and approval of meeting minutes.

i) The archiving and preservation of the committee's documentation and related to the clinical studies evaluated, in accordance with paragraph 7.

j) A procedure to declare an overcome incompatibility on a member of the "CEIm" and the warranties to ensure confidentiality in its internal operation.

4. Where CEIm does not gather the knowledge and experience necessary to evaluate a particular clinical study, it shall seek the advice of at least one expert non-committee person, who shall respect the principle of confidentiality. This advice will be specifically considered when:

a) The committee evaluates clinical research protocols with surgical procedures, diagnostic techniques, medical devices, or advanced therapies. In this case it will have the advice of at least one expert person in the procedure or technology to be evaluated.

b) The committee evaluates clinical trials that refer to subjects with special vulnerability. In this case it shall be provided with the advice of at least one person with experience in the treatment of the population to be included in the test and, where appropriate, in the treatment of the disease.

5. The principal investigator or collaborators of a clinical study may not participate in the evaluation, nor in the opinion of their own protocol, even if they are members of the committee. Where such circumstances arise, the record of the committee's assessment of the test shall be consistent with the fact that this principle has been respected.

6. Non-face-to-face meetings may be held by telephone, video-conference or any other similar system, so that CEIm members attend such a meeting by means of the appropriate system, provided that they are secured. the communication between them in real time and, therefore, the unit of act.

Each meeting of the CEIm will be collected in the corresponding minutes, at least the members, in-person or not, and assistant advisors, if any, will indicate that for each study evaluated the aspects covered by the applicable rules and the decision taken on each study shall be taken.

7. The committees shall keep all the essential documents relating to each clinical study evaluated during at least three years after the completion of the clinical study or for a longer period if the Spanish Medicines Agency and Sanitary Products in collaboration with the Autonomous Communities. The content of the clinical trial file shall be indicated in the instructions for the conduct of clinical trials in Spain to be published by the Spanish Agency for Medicinal Products and Health Products.

CHAPTER V

Presentation, validation, and procedure of evaluation and authorization of clinical trials with medicinal products

Section 1. Common Provisions

Article 17. Requirements for the conduct of clinical trials.

1. Clinical trials with medicinal products shall be subject to prior authorisation by the Spanish Agency for Medicinal Products and Sanitary Products, following a scientific and ethical assessment of Parts I and II.

2. In order to start a clinical trial with medicines in a centre, it will be necessary:

(a) The favourable opinion issued by a CEIm of the national territory as referred to in Article 24 which shall be unique and binding.

b) The resolution of the authorization of the Spanish Agency for Medicines and Health Products.

(c) The conformity of the address of the participating centre to be expressed by the signature of the contract between the sponsor and the centre referred to in Article 32. Only in clinical trials where the promoter/investigator belongs to the centre and no contract signature is required shall be specified the express conformity of the address of the participating centre.

This contract may be formalized at any time and shall be effective when the clinical trial is authorized by the Spanish Agency for Medicines and Health Products and has the favourable opinion of the CEIm for the performance of the contract. of the test at that centre.

3. Clinical trials with gene therapy medicinal products that produce modifications to the gene identity of the germline of the person are prohibited.

Article 18. Collaboration and exchange of information between the Spanish Agency for Medicines and Health Products and CEIm.

1. The Spanish Agency for Medicinal Products and Sanitary Products will establish mechanisms and procedures for collaboration and exchange of information in clinical studies with medicines and clinical research with medical devices with the CEIm, which shall be made public.

2. All this will be translated into a "memorandum of collaboration" that will identify and identify the responsibilities of the CEIm and the Spanish Agency for Medicines and Health Products, as well as those aspects that, according to the Articles 22 and the following shall be the subject of assessment and responsibility for each of them, in order to ensure the highest efficiency and guarantees in the assessment and to allow, in the multinational clinical trials carried out in the Union European, have a unique decision for Spain.

3. The "memorandum of collaboration" shall establish which parts of the application file shall be submitted in Spanish and which may be accepted in a language generally understood in the medical field as specified in the Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

Article 19. Exchange of information between the Spanish Agency for Medicines and Health Products and the Autonomous Communities.

1. The Spanish Agency for Medicinal Products and Sanitary Products shall establish with the competent bodies of the autonomous communities the framework for collaboration and a procedure for the exchange of information on clinical studies with medicinal products and clinical investigations with medical devices.

2. The instructions for the conduct of clinical trials in Spain published by the Spanish Agency for Medicinal Products and Health Products shall consist of the contact points of the autonomous communities to which the information is to be sent. While this process is not available.

Article 20. Aspects of a clinical trial that require evaluation.

1. The CEIm and the Spanish Agency for Medicines and Health Products will evaluate the documentation of the clinical trial.

2. The assessment shall be differentiated in two parts, referred to as Part I and Part II of the assessment report:

(a) Part I shall include the aspects listed in Article 6 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

(b) Part II shall include the aspects listed in Article 7 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014. The assessment related to the items referred to in paragraph 1 (h) of that Article 7 should include the forecasts for the collection, storage and possible future use of the biological samples of the test subjects obtained in the the centre itself or in collaborating centres, including samples of pre-selection of subjects, ensuring that no procedure is carried out to prevent the application of the provisions of Article 3.2 of Royal Decree 1716/2011, 18 November.

3. The Spanish Agency for Medicines and Health Products and CEIm will agree on the "collaboration memorandum" on the distribution of responsibilities for the assessment of applications.

4. In accordance with Article 29.5 of Royal Decree-Law 9/2014 of 4 July 2014 establishing quality and safety standards for donation, procurement, evaluation, processing, preservation, storage and distribution of human tissues and cells and the rules for coordination and operation for their use in humans, in the clinical trials of cell therapy, in addition to the provisions of paragraph 2, the Spanish Agency for Medicinal Products and Sanitary Products request to report to the National Transplant Organization. This report shall be issued in the form and time required to comply with the requirements laid down in Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

Section 2. First Authorization Procedure for a Clinical Trial

Article 21. Submission of requests and receipt of notifications.

1. The promoters shall submit their applications and communications and shall receive the notifications through the portal referred to in Article 80 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 ('the portal '). the EU "), addressed to the Spanish Agency for Medicines and Health Products and to the CEIm which has accepted the assessment.

2. The documentation to accompany the application for authorisation and opinion of the clinical trial is set out in Annex I to Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on the European guidelines in force and, where appropriate, in the instructions for the conduct of clinical trials in Spain which, under the development of that Annex I, are published by the Spanish Agency for Medicinal Products and Sanitary Products.

Article 22. Validation of the request.

1. The Spanish Agency for Medicinal Products and Sanitary Products shall assess whether or not the "clinical trial" character is accepted for the study and shall verify that the application is complete with respect to the documents in Part I for the assessment to which refers to Article 6 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

2. The CEIm shall verify that the application is complete with respect to the documents in Part II for the assessment referred to in Article 7 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014. of 2014.

3. The validation shall be carried out in such a way as to meet the deadlines and procedure provided for in Article 5 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

Article 23. Part I of the assessment report.

1. The Spanish Agency for Medicines and Health Products will be responsible for communicating part I of the evaluation report to the promoter, integrating those aspects that have been evaluated by the CEIm, so that the promoter is notified in the time limits and in accordance with the procedure referred to in Article 6 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

2. The participation of CEIm in the assessment of Part I shall be set out in the memorandum of collaboration referred to in Article 18, as well as the time limits for transmitting its report to the Spanish Agency for Medicinal Products and Health Products, in such a way that the above paragraph can be fulfilled.

3. In the case of an assessment coordinated by a notifying Member State, the information referred to in Article 8 (2) of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 shall be taken into account.

Article 24. Part II of the assessment report.

CEIm shall be responsible for drawing up Part II of the assessment report in such a way as to meet the deadlines and procedure laid down in Article 7 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

Article 25. Authorization resolution.

1. The head of the Directorate of the Spanish Agency for Medicines and Health Products within five days as provided for in Article 8 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, dictate resolution authorizing the clinical trial, authorizing it with conditions or denying its consent.

2. The judgment given shall terminate the administrative procedure and the person concerned may, in accordance with Articles 116 and 117 of Law No 30/1992 of 26 November 1992, institute a replacement for the purposes of the administrative procedure, Public Administrations and the Common Administrative Procedure, or administrative dispute, in accordance with Law 29/1998 of 13 July of the Jurisdiction-Administrative Jurisdiction.

3. The authorisation of the clinical trial shall be without prejudice to the application, where appropriate, of Law 9/2003 of 25 April establishing the legal regime for the contained use, voluntary release and marketing of genetically modified organisms.

Article 26. Modification of the conditions for the authorisation of clinical trials.

1. Any "substantial modification" under the conditions authorised for a clinical trial shall not be carried out without the prior favourable opinion of CEIm and the authorisation of the Spanish Agency for Medicinal Products and Sanitary Products.

However, if circumstances were given that could endanger the safety of the participating subjects, the promoter and the investigator shall take appropriate urgent measures to protect the subjects from any risk. immediate. The sponsor shall inform the Spanish Agency for Medicinal Products and Sanitary Products as soon as possible and the CEIm of those circumstances and of the measures taken.

2. As a general rule, CEIm and the Spanish Agency for Medicinal Products and Health Products will assess those aspects that have already been stated in the initial assessment report referred to in Articles 23 and 24, without prejudice that the 'memorandum of collaboration' referred to in Article 18 determines a different allocation of tasks.

3. The application shall be submitted to the Spanish Agency for Medicinal Products and Sanitary Products and to the CEIm which evaluated the initial application as referred to in Chapter III and Article 25 of Regulation (EU) No 536/2014. European and Council of 16 April 2014, in the European guidelines in force and, where appropriate, in the relevant part of the instructions for the conduct of clinical trials in Spain published by the Spanish Medicines Agency and Sanitary Products.

4. Validation and assessment of Part II of the substantial modification by the CEIm, where appropriate, shall be in accordance with the assessment deadlines and procedure laid down in Articles 20, 21 and 22 of Regulation (EU) No 536/2014. European Union and the Council of 16 April 2014.

5. The validation and assessment of Part I of the substantial modification by the Spanish Agency for Medicinal Products and Sanitary Products shall be in accordance with Articles 17, 18, 21 and 22 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

6. The authorisation resolution shall be issued taking into account the provisions of Articles 19, 20 and 23 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 and as set out in Article 25 of this Royal Decree. However, in the case of relevant amendments which only involve changes in aspects included in Part II of the assessment report, the authorisation shall be deemed to have been granted or refused on the date on which the CEIm informs the sponsor of its opinion. with the conclusions of Part II of the assessment report.

Article 27. Suspension and revocation of the authorisation of the clinical trial.

1. The authorisation of the clinical trial shall be suspended or revoked, either on its own initiative or at the request of the sponsor, by means of a decision of the Spanish Agency for Medicinal Products and Sanitary Products in the cases referred to in Article 77 of the Regulation. (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

2. The decision to suspend or revoke the approval of the test shall be adopted by the Spanish Agency for Medicinal Products and Products subject to the instruction of the appropriate procedure, with a hearing to the person concerned to give an opinion on the seven calendar days to be counted from the notification of the start of the procedure.

Once the above resolution has been adopted, the Spanish Agency for Medicines and Health Products will notify the decision taken, with an express indication of the reasons, to the European Commission, to the European Commission of Medicinal products, to the health authorities of the autonomous communities and to the health authorities of the other Member States.

3. The health authorities of the autonomous communities may issue a decision on the precautionary suspension of the clinical trial in the cases provided for in paragraph 1 and shall notify it immediately, together with a duly detailed reasoned report, to the the Spanish Agency for Medicinal Products and Sanitary Products, which, in accordance with paragraph 2, shall resolve the suspension or revocation of the authorisation of the test or, where appropriate, the lifting of the precautionary measure.

4. The judgment given shall terminate the administrative procedure and the person concerned may bring the replacement of the replacement of the goods in accordance with the provisions of Articles 116 and 117 of Law No 30/1992 of 26 November 1992. administrative-administrative, in accordance with Law 29/1998 of 13 July.

Article 28. Corrective measures to be taken by the Spanish Agency for Medicines and Health Products.

1. The Spanish Agency for Medicinal Products and Sanitary Products, on its own initiative, or at the justified request of the CEIm may require the sponsor to modify any aspect of the test.

2. The decision requiring the amendment of any aspect of the test shall be adopted after the appropriate procedure has been given, with a hearing to the person concerned, who shall decide within seven calendar days from the date of notification of the start of the procedure.

3. The judgment given shall terminate the administrative procedure and the person concerned may bring the replacement of the replacement of the goods in accordance with the provisions of Articles 116 and 117 of Law No 30/1992 of 26 November 1992. administrative-administrative, in accordance with Law 29/1998 of 13 July.

Article 29. Communication of serious breaches.

1. Serious breaches of the authorised protocol or of this royal decree which have occurred in Spain must be communicated by the sponsor without undue delay and at the latest within seven calendar days from the date on which the knowledge of the non-compliance, the Spanish Agency for Medicinal Products and Sanitary Products and the CEIm by the means referred to in Article 21.

2. For these purposes, a serious non-compliance shall mean that which can significantly compromise the safety and rights of the test subjects or the reliability and robustness of the data obtained in the clinical trial.

3. The Spanish Agency for Medicines and Health Products shall inform the health authorities of the autonomous communities of serious non-compliances directly affecting centres belonging to their community.

Article 30. Completion, temporary cessation and early completion of a clinical trial and presentation of results.

1. The sponsor shall communicate the date of completion of the clinical trial in Spain, the date of completion in all the countries in which the test has been carried out, and any temporary cessation of the test and the results of the test according to the time limits. and the procedure referred to in Articles 37 and 38 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

2. In the event of the anticipated completion of the test, the communication shall indicate the reasons for such action and specify the follow-up measures without prejudice to the subsequent submission of the results report required in Annexes IV and V of the Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014. This information shall be transmitted to the health authorities of the Autonomous Communities in accordance with Article 19. The completion date of the clinical trial and the reasons for the anticipated completion should be published by the Spanish Agency for Medicines and Health Products.

CHAPTER VI

From continuation of treatment after trial

Article 31. Continuation of treatment with a medicinal product without a marketing authorisation in Spain after the end of the trial.

Any continuation in the administration of an investigational medicinal product without marketing authorisation in Spain to subjects who have completed their participation in a clinical trial, as long as they are not marketed in a manner The medicine in Spain for these conditions of use will be governed by the rules established in Royal Decree 1015/2009 of 19 June, which regulates the availability of medicines in special situations. The supply of these medicinal products must comply with the provisions of paragraph (f) of Article 39.3, if the sponsor obtains any information from the administration and use of the said medicinal product under these conditions.

CHAPTER VII

Economic aspects

Article 32. Economic aspects of the clinical trial.

1. All economic aspects related to the clinical trial shall be reflected in a contract between the sponsor and each of the centres where the test is to be carried out.

An economic memory of the project will be transmitted to CEIm, which includes all aspects reflected in the contract of all the participating centers.

2. The competent health administrations of each health service shall establish the common requirements and financing conditions and agree on a single contract model valid for the entire National Health System. This model of a single contract shall be drawn up in accordance with the general principles of coordination agreed by the Interterritorial Council of the National Health System and shall, prior to its use, be counted with the approval of this.

3. The contract shall include:

(a) The initial budget of the test, which shall specify the indirect costs to be applied by the centre, as well as the extraordinary direct costs, considering as such those expenses other than those incurred if the subject have not participated in the test, such as:

1. Additional Analysis and Complementary Scans.

2. º Changes in the duration of care for the sick.

3. Reimbursement for expenses to patients.

4. Purchase of apparatus and compensation for test subjects and researchers.

b) The terms and deadlines for payments.

c) Any other subsidiary liability that the parties contract, in accordance with the conditions set forth in each center.

4. No additional amounts may be required for the centres provided for in the economic report submitted to the CEIm, except where they are approved in accordance with the provisions of Article 31 and referred to in Article 16.

Article 33. Fees.

1. In accordance with Article 87 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, the payment of a single fee shall be required for the assessment of a clinical trial, irrespective of whether they are different. bodies involved in the assessment. This fee will be laid down in the legislation in force in a transparent manner and on the basis of the principle of cost recovery. The sponsor shall pay it to the Spanish Agency for Medicines and Health Products which shall be responsible for transferring the part of the sponsor to the CEIm.

2. In no case may the payment of fees which are not covered by the corresponding legal framework by the centres in respect of the conduct of the trial or in relation to the performance of any of the functions of a CEIm be required. related to the assessments referred to in Article 12.

3. Clinical studies that correspond to the definition of "clinical non-commercial research" will benefit from the exemptions of reduced rates or rates, as provided for in the recast text of the Law on Guarantees and Use. the rational use of medicines and medical devices, approved by the Royal Legislative Decree 1/2015 of 24 July.

CHAPTER VIII

Medicines used in a clinical trial

Article 34. Manufacture and import of investigational medicinal products or auxiliary medicinal products.

1. The manufacture and import of investigational medicinal products for use in the field of a clinical trial may be carried out only by those manufacturers and importers of medicinal products which have the appropriate authorization to use them. In accordance with the provisions of Royal Decree 824/2010 of 25 June 2010 on the control of pharmaceutical laboratories, manufacturers of active substances for pharmaceutical use and the external trade in medicinal products and medicinal products in the research.

2. Such authorisation shall not be required for the re-labelling or reconditioning, if it is carried out in an approved pharmacy service of a participating centre, provided that the investigational medicinal products are intended to be used only in hospitals, health centres or clinics participating in the same clinical trial.

3. Where in the context of a specific clinical trial the sponsor of which is a researcher or a group of researchers an authorised pharmacy service of a participating centre wishes to carry out a manufacturing operation other than those envisaged You will have to request prior authorisation from the Spanish Medicines and Health Products Agency and only the medicinal product may be used in the specific clinical trial. The Spanish Agency for Medicinal Products and Sanitary Products will agree with the autonomous communities on the procedures for verifying the correct manufacturing of medicinal products applicable in these cases.

4. They also do not need to have the authorization as a manufacturer and importer of medicinal products referred to in paragraph 1, the centres linked to the National Health System where advanced therapy medicinal products are developed in the research phase. for use in clinical trials authorised by the Spanish Agency for Medicinal Products and Sanitary Products, without prejudice to the requirement of specific quality standards.

5. In the manufacture of investigational medicinal products, the correct manufacturing rules of the European Union should be followed.

6. The manufacturer must have a permanent and continuous provision of a qualified person or a technical director, in accordance with the provisions of Royal Decree 824/2010 of 25 June 2010. The responsibilities of this qualified person or technical director are set out in the aforementioned royal decree.

In the case of an investigational medicinal product coming from a third country and having a marketing authorisation in that country, where the documentation for which each batch of products is certified cannot be obtained. manufactured according to good manufacturing practice at least equivalent to those mentioned above, the qualified person or technical director shall ensure that each batch of manufacture has been the subject of all analyses, tests or relevant and necessary checks to confirm their quality.

7. The authorization for the importation of the investigational medicinal products, for use in the field of a clinical trial, shall be understood to be granted if the Spanish Agency has received the request of the Spanish Agency for a period of 60 calendar days from the date of receipt of the request. Medicines and Sanitary Products do not communicate motivated objections to the promoter, provided the trial has been authorised.

8. The application for the authorisation of import of investigational medicinal products may be requested in unit of act with the application for the clinical trial to which they are intended.

The authorisation of manufacture or import of blood products, narcotic drugs or psychotropic substances shall be governed by their specific legislation in this field.

Article 35. Tagged.

1. The labelling of medicinal products in research and/or auxiliaries shall be in accordance with Articles 66 to 68 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, taking into account the provisions of Articles 66 to 68 of Regulation (EU) No 536/2014. detailed guidelines for the correct manufacturing rules applicable to investigational medicinal products in the European Union and, where appropriate, the instructions of the Spanish Agency for Medicinal Products and Sanitary Products.

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

Article 36. Acquisition of medicinal products for clinical trials.

1. Wholesale warehouses and pharmaceutical laboratories may provide the sponsor of an approved clinical trial with medicinal products included in that test, on presentation by the same of the authorisation issued by the Spanish Agency of Medicinal products and Sanitary products for testing.

2. Where the medicinal products to be used in a clinical trial come from a third country, account shall be taken of the provisions of Article 34 as regards the importation of investigational medicinal products.

Article 37. Medication left over from a clinical trial.

1. In the case of investigational medicinal products and ancillary medicinal products marketed in Spain, after the end of the clinical trial they may be used in the usual clinical practice, under the conditions laid down in their marketing authorisation, Any excess packaging that is unaltered, that is, that has not been modified in either its primary or secondary packaging, and always under express and prior authorisation by the sponsor.

2. In the case of investigational medicinal products not placed on the market in Spain, after the end of the clinical trial the sponsor may request the use of the remaining unaltered packaging for the continuation of the treatment outside the agreement test as referred to in Article 31.

CHAPTER IX

Clinical Good Practice Standards

Article 38. Standards of good clinical practice.

1. The sponsor of a clinical trial and the investigator shall ensure that the clinical trial is conducted in accordance with the protocol and with the principles of good clinical practice.

2. Without prejudice to other provisions, the sponsor and the investigator, when drawing up the protocol and implementing this royal decree and protocol, shall take due account of the quality standards and guidelines of the International Conference of Harmonisation (ICH) on good clinical practice.

3. In the case of clinical trials with advanced therapy medicinal products, specific clinical practice guidelines for advanced therapy medicinal products will be further followed.

4. The Spanish Agency for Medicines and Health Products will make publicly available the guidelines on good clinical practice provided for in this article.

Article 39. Promoter.

1. The sponsor or his legal representative shall be established in one of the Member States of the European Union.

2. It is for the sponsor to sign the requests for opinion and authorisation addressed to CEIm and the Spanish Agency for Medicines and Health Products.

3. They are the promoter's responsibilities:

(a) Establish and maintain a quality assurance and control system, with standard written work procedures, so that the tests are carried out and the data generated, documented and reported in accordance with the protocol, the rules of good clinical practice and the provisions of this royal decree. Standard work procedures should be available to ensure quality standards at all stages of the documentation of an adverse event, data collection, validation, evaluation, archiving, communication and monitoring.

b) Sign, together with the relevant investigator, the protocol and any of its amendments.

c) Select the most appropriate investigator based on their available qualification and means, and ensure that the researcher will conduct the study as specified in the protocol.

d) Provide the basic and clinical information available from the research product and update it throughout the trial.

e) To request the opinion of the CEIm and the authorization of the Spanish Agency for Medicines and Health Products, as well as to inform them of the start of the trial, serious breaches of the protocol, and other necessary information, by collecting the authorisations that they carry out, without prejudice to the communications to be made to the autonomous communities, in accordance with Article 19.

f) To provide free of charge to investigational medicinal products, to ensure that the correct manufacturing standards have been complied with and that the samples are properly packaged and labelled. It is also responsible for the preservation of samples and their manufacturing and control protocols, for the registration of the samples delivered and to ensure that a proper handling procedure is in place at the centre where the test is carried out. conservation and use of such samples.

In clinical trials whose promoter is a researcher of the centre or a non-profit entity of a scientific nature, or in those where there is common agreement with the direction of the centre where the test is to be carried out clinical, other forms of supply may be agreed with the centre, especially when the treatment of patients in the test, or part of it, is the one they would receive in case they have decided not to participate in the trial.

g) Ensuring that the participation of a subject in the clinical trial will not entail a cost for the additional one it would have had to deal with in the context of the usual clinical practice.

h) Designate the monitor to monitor the running of the test.

i) Communicate suspicions of serious and unexpected adverse reactions in accordance with Articles 49 to 53.

(j) Provide the investigator, the Spanish Agency for Medicines and Health Products and the CEIm immediately with any information of importance related to the clinical trial to which they have access during the same.

k) comply with the obligations for damages in the terms set out in Article 9. Provide the investigator with legal and economic coverage in these cases except where the injury is a consequence of negligence or malpractice of the investigator.

l) To agree with the researcher on the obligations regarding data processing, reporting and publication of results. In any case, the sponsor is responsible for producing the final report and the annual reports of the trial and communicating them to the appropriate person.

m) The promoter shall have a contact point where the test subjects can obtain further information on the test, which may optionally be delegated to the investigator.

n) Meet the obligations imposed by the Spanish Registry of Clinical Studies for the publication of the trials of which he is a promoter.

n) Agree with the investigator, the management of the center and the CEIm alternative distribution modes in cases where the center does not have a Pharmacy Service. In this case, it will be possible to send the investigational medicinal products by the promoter to the research center assuming the investigator of that center the responsibilities regarding the correct administration, custody and delivery of these medicines, as specified in the study protocol.

4. The sponsor of a clinical trial may delegate all or part of his/her tasks to a particular contract research organisation (CRO), institution or body, which shall have a quality assurance and control system.

5. The obligations of the sponsor established in the rules of good clinical practice that have been delegated shall apply to the individual, CRO, company, institution or body contracted. However, in such cases, the sponsor shall remain responsible for ensuring that the conduct of the clinical trial and the final data generated in that study are in accordance with the provisions of this royal decree. Any delegation of functions of the sponsor in relation to a clinical trial should be specifically documented in a contract between the two parties.

6. The promoter and investigator may be the same person.

7. If a clinical trial has more than one promoter, all co-promoters shall bear the responsibility of the sponsor established in this Article unless they decide otherwise in a contract to establish their respective responsibilities. If the contract does not specify which co-promoter a particular liability is attributed to, it falls to all of them.

8. Without prejudice to paragraph 7, all co-promoters shall be jointly responsible for designating:

(a) A promoter responsible for the performance of the promoter's obligations as regards the authorisation procedures laid down in Chapter V.

b) A promoter responsible for being the point of contact that receives and answers all questions from the test subjects, the researchers, the CEIm or the Spanish Agency for Medicines and Health Products related to the clinical trial.

c) A promoter responsible for applying the corrective measures imposed on you.

Article 40. Monitor.

1. They are monitor responsibilities:

(a) Work in accordance with the promoter's standard working procedures, visit the investigator before, during and after the test, depending on the type of study, to check compliance with the protocol, that the data are recorded correctly and completely, as well as ensuring that the informed consent of all subjects has been obtained prior to their inclusion in the trial.

b) Ensure that the researchers and the center where the research is conducted are suitable for this purpose during the period of testing.

c) Ensure that both the principal investigator and his/her collaborators have been adequately informed and at all times ensure rapid communication between investigator and promoter, especially in the field of supervision of the safety of the test.

d) Verify that the investigator complies with the protocol and all of its approved modifications.

e) Check that the storage, distribution, return, and documentation of investigational drugs is safe and adequate.

f) Rissue to the promoter reports of monitoring visits and all relevant contacts with the investigator.

2. The monitor shall in no case be part of the research team.

Article 41. Investigator.

1. The investigator directs and takes responsibility for the practical implementation of the clinical trial in a given field.

2. Only a doctor or a person exercising a recognised profession in Spain may act as a researcher in order to carry out research on the basis of his or her scientific training and experience in the required health care.

3. They are the researcher's responsibilities:

a) Sign the test protocol together with the promoter.

b) To thoroughly know the properties of investigational drugs.

c) Ensure that informed consent is collected in accordance with the provisions of this royal decree.

d) Collect, record and report the data correctly and ensure its veracity.

e) Follow the instructions regarding the communication of adverse events established in the protocol.

f) Immediately communicate serious breaches to the protocol to the promoter.

g) Ensure that all persons involved respect the confidentiality of any information about the subjects of the trial, as well as the protection of their personal data.

h) Report regularly to the CEIm of the test march.

i) Corresponsibility to the developer of the final report of the test, giving your agreement to your signature.

4. Each person involved in the conduct of a trial shall be trained by their qualifications, training and experience to perform their tasks. The researcher will also ensure that his collaborators are informed about the protocol, about the investigational drugs, and about their roles in the study.

5. The principal investigator may delegate tasks to the members of the team of investigators. Such delegation does not exempt the investigator from being responsible for carrying out the test in accordance with the legislation in force. The delegation of responsibility of the investigator for each clinical trial should include not only the participating staff but also the collaborating researchers who have delegated the development of some function, as well as their duties and responsibilities. If there are changes, they must be reflected.

6. The contract staff must be authorised by the management of the health centre, specifying whether or not they have access to the medical history and personal data of the subjects included in the trial. This authorization can be materialized in two ways, by:

a) The signing of a contract, if it is personnel hired by the center.

b) Independent access document if you are a third-party contract staff.

Article 42. Publications.

1. The promoter is obliged to publish the results, both positive and negative, of the clinical trials, preferably in scientific journals before being disclosed to the non-sanitary public, regardless of the obligations of the publication of the report of the results in the Spanish Register of Clinical Studies (REEC) and of the provisions of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

2. Where studies and research work on medicinal products are made public, the funds obtained by the author, by or for their implementation, and the source of funding shall be recorded.

3. The anonymity of the subjects participating in the trial shall be maintained at all times.

4. They will not be released prematurely or sensationalist treatments of efficacy not yet determined, nor will it be exaggerated. No advertising shall be given to intermediate results which may compromise the reliability of the final test results.

5. The advertising of medicinal products for human use in research is strictly prohibited, as set out in the recast text of the Law on the guarantees and rational use of medicinal products and medical devices, in Royal Decree 1416/1994, Council Regulation (EEC) No 255/88 of 25 June 1996 on the advertising of medicinal products for human use, Royal Decree 1907/1996 of 2 August 1996 on the advertising and commercial promotion of products, activities or services with a intended health purpose, and in the Law 34/1988, of 11 November, General of Advertising.

6. In all cases, to make public the general results of the investigations once concluded, the guidelines of the European Commission and, where appropriate, the instructions of the Spanish Agency for Medicinal Products and Products will be followed. Sanitary.

7. Where a sub-study of a clinical trial is completed at a later date than the rest of the test, the summary of its results shall be published in the year following its completion, without delay in the submission of the results. of the rest of the test.

Article 43. Content and conservation of the clinical trial master file.

1. The master file of the clinical trial shall comply with Articles 57 and 58 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014. Its content shall take account of the additional guidance published by the European Commission.

2. The sponsor and the investigator shall keep the content of the master file in paper or digital format for each clinical trial for at least 25 years after the end of the test, or for a longer period if available to others. applicable requirements, such as in the case that the study is presented as a basis for the registration of a medicinal product in which Annex I to Royal Decree 1345/2007 of 11 October 2007, or an agreement between the sponsor, the investigator and the center.

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

4. The clinical history of the subject of the test shall be kept in accordance with the provisions of Law 41/2002 of 14 November, and in accordance with the maximum period permitted by the hospital, institution or private consultation.

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

6. The sponsor shall appoint the persons in his/her organisation responsible for the files and the access to the files shall be limited to the persons designated.

7. The supports used to preserve the essential documents shall, in general, be in electronic form and must ensure that the documents remain complete and legible during the intended period of storage and are the provision of the competent authorities in the event of their request. Any modification of the records shall be traceable, allowing to know the initial and corrected data, as well as the date and signature of the author.

This documentation should be archived, preferably grouped by protocols, in a place that ensures the confidentiality of the information during the required file time.

In the event that there are open court proceedings, the essential documents will be preserved as long as there is no firm judicial decision.

CHAPTER X

Verifying compliance with good clinical practice standards

Article 44. General provisions on inspection.

1. The Spanish Agency for Medicinal Products and Health Products and the competent health authorities of the autonomous communities, within the scope of their respective competences, will verify the application of this royal decree, of the rules of good clinical practice and the correct manufacturing standards in clinical trials carried out in Spain, through the appropriate inspections.

2. The authorities of the General Administration of the State and the competent autonomous communities shall assist each other for the purpose of these inspections.

3. In the activity of inspection of good clinical practice, the requirements regarding the protection of personal data, as laid down in Organic Law 15/1999 of 13 December, must be complied with.

4. The inspections will be carried out in accordance with the guidelines developed at European level to support the mutual recognition of the findings of the inspections within the European Union.

5. The relationship with the competent authorities of the Member States of the European Union regarding the inspection of good clinical practice shall be carried out through the Spanish Agency for Medicinal Products and Health Products.

6. Where a health authority of a Member State of the European Union requests information relating to a reasoned written inspection, the Spanish Agency for Medicinal Products and Health Products shall transmit the relevant report. To this end, he shall request the report to the competent authorities of the autonomous community where the centre is situated.

7. Similarly, where it is necessary to request information from another Member State on an inspection carried out in that Member State, the Spanish Agency for Medicinal Products and Health Products shall be sent to the competent body of that State in writing. motivated, and will require the relevant information.

8. The competent authorities of third countries to carry out inspections of good clinical practice in Spain shall notify the Spanish Agency of Medicinal Products and Sanitary Products in sufficient time. The sponsor shall be responsible for informing the competent authority of the third country of this notification obligation. The Spanish Agency for Medicines and Health Products will report the inspection to the autonomous community where the center is to be inspected.

9. The Spanish Agency for Medicinal Products and Sanitary Products will inform the European Medicines Agency of the inspections carried out in Spain and its results. To this end, the Autonomous Communities shall send to the Spanish Agency for Medicinal Products and Health Products the information of the inspections carried out in the format agreed upon in the Technical Inspection Committee.

Article 45. Inspection procedure.

1. The inspections shall be carried out by duly qualified and appointed inspectors for that purpose in the places relating to the conduct of clinical trials and, inter alia, in the centre or centres where the clinical trials are carried out. testing, at the place of manufacture of the investigational medicinal product, any laboratory of analysis used in the clinical trial, in the CEIm, as well as in the facilities of the promoter and/or of the research organisations or undertakings involved by contract in the performance of the test.

2. At the end of each inspection, the inspectors shall draw up a regulatory inspection report to be signed by the inspector (s) acting as well as by the inspectors. It shall contain the most relevant facts and findings that have resulted from the inspection actions.

3. The inspectors will then draw up a report on compliance with good clinical practice and the requirements set out in this royal decree which will be in line with the European format agreed at Community level. Before adopting the report, the relevant inspected entity shall be given the opportunity to submit comments to it.

4. This report shall be made available to the inspected parties, the competent authorities in Spain and the sponsor, safeguarding the confidential aspects. Upon reasoned request, the report may be made available to the CEIm concerned, if it has not been directly subject to the inspection, as well as to the health authorities of the European Union, the European Medicines Agency and the health authorities with which agreements are in place.

5. In the event that serious non-compliance has been found in the inspection, as defined in Article 52.2 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, or has resulted in the adoption of the Precautionary measures referred to in Article 109 of the recast of the Law on the guarantees and rational use of medicinal products and medical devices, the health authority which adopted the precautionary measure must immediately inform the Commission of the the promoter, the CEIm and the other health authorities according to their competence.

CHAPTER XI

Communications

Article 46. Information systems.

1. The Spanish Agency for Medicinal Products and Sanitary Products shall be the national point of contact established by Article 83 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

2. All communications between the actors involved in the application, evaluation and authorisation of clinical trials with medicinal products shall be carried out, where available, through the EU portal and the EU database to which they are available. referred to in Articles 80 and 81 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

3. Until the information systems referred to in paragraph 2 are available or as a complement to those systems:

(a) The Spanish Agency for Medicinal Products and Sanitary Products shall include in the European clinical trial database (EudraCT) data relating to clinical trials with medicinal products for human use that are carried out in the national territory.

(b) The Spanish Agency for Medicinal Products and Sanitary Products shall maintain the information system for clinical trials with medicinal products for human use that are carried out in the national territory. This information system will serve as the sole point of contact for the promoter in everything related to its clinical trials, by redirecting the information, as appropriate, to the Spanish Agency for Medicines and Health Products and to the CEIm, as well as the competent authorities of the Autonomous Communities and the REEC.

4. The information system referred to in the previous paragraph shall also serve for all types of communication and transmission of decisions between the Spanish Agency for Medicinal Products and Sanitary Products and CEIm with the sponsor. as the communications and transmission of opinions or other documents between the CEIm and the Spanish Agency for Medicines and Health Products.

Article 47. Spanish registry of clinical studies.

1. The Spanish Agency for Medicines and Health Products will keep a register of clinical studies with medicinal products for human use on its website.

2. The REEC will include the following information:

(a) In a mandatory manner, clinical trials with medicinal products for human use that are authorised by the Spanish Agency for Medicines and Health Products, in accordance with this royal decree.

(b) The post-authorisation studies of an observational type to be carried out and have been classified by the Spanish Agency for Medicines and Health Products.

c) On a voluntary basis, as well as other similar databases, other types of clinical studies promoted by public or private entities, national or international, as long as they have at least one participating institution Spain, which includes cases or, not including cases, has a Spanish contribution which is considered to be significant.

3. The registration of a clinical trial or study in the REEC shall be compatible with its inclusion in other national or international registers. The REEC shall include forward-looking information in its field of application since its implementation.

4. The REEC will include for each study the related information in the Annex, which includes the data set required in the international clinical trial records platform of the World Health Organization. The Spanish Agency for Medicinal Products and Sanitary Products shall publish the correspondence between these fields and those of the application form for the authorisation of the clinical trial referred to in the case of clinical trials with medicinal products. as the application form for the classification of observational studies.

5. In all cases, the promoters will have to make public in this register the results of the recorded investigations once concluded. To this end, the standard and time limits set out in the guidelines of the European Commission and, where appropriate, the instructions published by the Spanish Agency for Medicines and Health Products shall be followed.

Article 48. Procedure for the publication of a study in the REEC.

1. The REEC is aimed at providing reliable and comprehensible information to citizens, so the information contained in some fields may be limited in terms of extension and should be in plain language and accessible to the public. citizen without special scientific knowledge.

With the objective of the REEC being included in the International Platform of Clinical Trials Records of the World Health Organization, all information will be available in English and Spanish.

2. The sponsor shall be responsible for the quality, accuracy and periodic update of all the information in the study to be included in the REEC. The Spanish Agency for Medicines and Health Products shall verify before its inclusion that the data are complete and appropriate for its objectives.

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

4. In general, the publication of clinical studies shall be carried out in accordance with one of the procedures set out in paragraphs 5, 6 and 7.

5. The information from clinical trials with medicinal products, common with the European Union Registry of Clinical Trials, will be published by the Spanish Agency for Medicines and Health Products at the time of the authorisation of the trial. The sponsor of a clinical trial with medicinal products shall have a maximum period of 14 calendar days from the notification of this authorisation to complete the necessary additional information in the REEC, with a brief summary of the test and participating centers.

6. For the entry in the REEC of post-authorisation studies of an observational type, the sponsor shall include the data of the study at the time of its commencement or within a maximum period of fourteen calendar days after obtaining the authorisations. in accordance with the rules in force for those studies requiring prior authorisation.

7. The sponsor of the type of studies referred to in Article 47.2.c) may voluntarily opt for the inclusion of his data in the REEC once the study has a favourable opinion of a CIS and, where appropriate, the approval of the (i) The ERC's opinion will be sent to the Spanish Agency for Medicines and Health Products when applying for registration.

However, the Spanish Agency for Medicines and Health Products reserves the ultimate authority to verify the information received and to accept its publication in the "REEC" or, in the event that the information cannot be validated, not including it.

In any case, the Spanish Agency for Medicines and Health Products will publish a document that relates the rules to be completed for the enrollment of the studies in the REEC.

8. The Spanish Agency for Medicinal Products and Sanitary Products may decide to make public a partial information on a clinical trial or a post-authorisation study of an observational type in which the sponsor has failed to comply with the time limits for the information, expressly stating the data of the sponsor as well as the reasons why the information in the register is partial. And this would be independent of the exercise of those sanctioning actions that could take place, in application of the legislation in force.

9. It is the responsibility of the sponsor to regularly update the information included in the REEC. This update will be mandatory with respect to the start date of the study in Spain, the participating centres, the date of completion of the recruitment in Spain, the substantial modifications that will entail a change in the data included in the registration and the date of completion of the study in Spain. The update will be carried out on a global basis and, in any case, on an annual basis until the completion of the study and the publication of its results.

CHAPTER XII

Surveillance of the safety of investigational drugs

Article 49. Obligations of investigators in the recording and reporting of adverse events.

1. The investigator shall record and document any adverse events or anomalous laboratory results which the protocol considers crucial for the safety assessment and shall communicate them to the sponsor in accordance with the communication requirements. and within the time limits specified in the protocol, as referred to in Article 41 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

2. The investigator shall inform the sponsor of serious adverse events without undue delay and within 24 hours of the date on which he becomes aware of such events, except that for certain events Serious adverse events, the protocol provides that no immediate communication is required. The investigator shall, where appropriate, send the sponsor a follow-up report to enable him to assess whether the serious adverse event has an impact on the benefit-risk relationship of the clinical trial. In the initial and follow-up communications, the test subjects shall be identified only by the identification code of the subject in the test, specific to each of them.

3. In the event that the death of a participant in a clinical trial has been reported, the investigator shall provide the sponsor and the CEIm with any additional information requested.

4. If the investigator is aware of a serious adverse event that has an alleged causal relationship to the investigational medicinal product, which has occurred after the end of the clinical trial in a subject treated by the investigator, sponsor without undue delay such a serious adverse event.

5. In any event, account shall be taken of the provisions specified in the guidelines of the European Commission or, where appropriate, in the procedures laid down in the instructions for the conduct of clinical trials in Spain published by the Agency. Spanish Medicines and Healthcare products.

Article 50. Other obligations of the sponsor in the registration, assessment and communication of adverse events.

1. The sponsor shall keep a detailed record of all adverse events reported to him by the investigators. These adverse events will be presented to the Spanish Agency for Medicines and Health Products when requested.

2. The promoter has an obligation to continuously assess the balance between the benefits and risks of the trial, including a continuous assessment of the safety of investigational medicinal products using all the information at their disposal. It must also communicate without undue delay within 15 calendar days the Spanish Agency for Medicinal Products and Sanitary Products and the CEIm, by the means referred to in Article 21, any information that will affect in an important way the benefit/risk ratio of the test, with the exception of suspected serious and unexpected adverse reactions reported in accordance with Article 51. Such communication shall be carried out in accordance with the guidelines of the European Commission or, where appropriate, with the procedures laid down in the instructions for the conduct of clinical trials in Spain published by the Spanish Agency of Medicines and Healthcare products.

3. The sponsor shall promptly inform the investigators of any important information which may adversely affect the safety of the subjects or the conduct of the test. The communication of such information shall be concise and practical. The communication shall be in accordance with the criteria and procedure specified in the European Commission guidelines.

Article 51. Notification of suspected serious and unexpected adverse reaction to the Spanish Agency for Medicines and Health Products.

1. The sponsor shall notify the Spanish Agency for Medicinal Products and Sanitary Products of all suspected serious and, at the same time, unexpected adverse reactions associated with the investigational medicinal products of which they have been informed, that they have occurred in the clinical trial, whether they occur in Spain or in other countries. In addition, suspected serious and, at the same time, unexpected adverse reactions occurring outside the test shall be reported in accordance with the criteria laid down in the European Commission guidelines.

2. In all cases, such notification shall be made through the Eudravigilance_CTM European database.

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

(a) In case of suspected serious and unexpected life-threatening or life-threatening adverse reactions, as soon as possible and in any event within seven days after the sponsor has become aware of the reaction.

(b) In case of suspected serious and unexpected non-life threatening or non-life threatening adverse reactions, no later than 15 days after the sponsor has become aware of the reaction.

(c) In case of suspected serious and unexpected serious or life-threatening adverse reactions, which have not initially been considered as such, as soon as possible and in any event not later than seven days later that the promoter has been aware that the reaction is fatal or life-threatening.

Where necessary to ensure rapid notification, the sponsor may make an incomplete initial notification which shall be completed as soon as possible within eight days.

4. The notification of serious and unexpected adverse reactions by the sponsor to the Spanish Agency for Medicinal Products and Health Products shall, in any event, comply with the criteria and the procedure specified in Articles 42, 45 and 46 of the Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

Article 52. Exchange of information on clinical trials with the competent bodies of the Autonomous Communities.

1. The Spanish Agency for Medicines and Health Products will provide a system whereby suspected adverse reactions, which are both serious and unexpected, associated with the investigational medicinal product and which have occurred in patients included in the clinical trial in Spain are available to the competent organs of the autonomous communities in real time through the clinical trial information system.

2. As long as a system for the exchange of electronic information valid for all autonomous communities, as referred to in Article 19, is not available, the notification to the autonomous communities by the sponsor shall be carried out according to the criteria to be set out in the relevant instructions of the Spanish Agency for Medicines and Health Products.

Article 53. Annual security report and other security reports.

1. Clinical trial promoters shall prepare an annual safety report assessing the safety of the investigational medicinal product taking into account all available information. That report shall be communicated to the Spanish Agency for Medicinal Products and Sanitary Products and to CEIm.

2. Irrespective of the annual safety report, the sponsor shall prepare an 'ad hoc' assessment report whenever there is a relevant safety concern. This report shall be submitted immediately to the Spanish Agency for Medicinal Products and Sanitary Products and to CEIm as indicated in the previous paragraph.

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

4. The clinical trial promoters in which the investigational medicinal products, excluding placebos, are authorised and, in accordance with the protocol of the clinical trial, are used in accordance with the terms of the marketing authorisation. submit a simplified report in accordance with the instructions for conducting clinical trials in Spain to be published by the Spanish Agency for Medicines and Health Products.

CHAPTER XIII

Violations

Article 54. Administrative infringements in the field of clinical trials.

They shall constitute administrative infringements as provided for in Chapter II of Title IX of the recast of the Law on the guarantees and rational use of medicinal products and medical devices, and shall be sanctioned in accordance with the provisions of this Directive. set out in Article 114 of that same recast text.

Additional disposition first. Ethical Committees of Clinical Research.

1. Within two years from the entry into force of this royal decree, the Ethical Committees of Clinical Research may be accredited as CEIm by the competent health authorities of the autonomous communities, taking into account the criteria set out in Chapter IV.

2. Once the two-year term has elapsed, those Ethical Research Committees that are not accredited as CEIm will be able to continue to assume those functions of the Research Ethics Committees not related to the assessment of clinical studies with medicinal products or medical devices until the forecasts laid down in the third transitional provision of Law 14/2007 of 3 July are met.

3. References to the Ethical Research Committees provided for in the recast text of the Law on the guarantees and rational use of medicinal products and medical devices shall be understood as being carried out by CEIm in the terms provided for in this real decree.

Additional provision second. Observational studies.

Without prejudice to the provisions of Chapter IV and Articles 18, 47 and 48, the observational studies defined in paragraph (k) of Article 2.1 shall be governed by their specific rules.

Additional provision third. Clinical trials with medical devices.

1. Clinical investigations with medical devices shall be governed by the ethical, methodological and protection principles of the test subjects referred to in this royal decree, taking into account the requirements of the product regulations health.

2. The CEIm will deliver an opinion on clinical research with medical devices. To this end, account shall be taken, in particular, of the provisions of Article 16.4 (a). When these investigations are carried out in several centres, the opinion shall be issued by a CEIm of the national territory and shall be unique and binding.

3. The initiation of clinical investigations with medical devices bearing the CE marking and using the same indications as provided for in the conformity assessment procedure shall be notified to the Spanish Agency for Medicinal Products and Sanitary Products provided that in these investigations there is a practice of intervention that modifies the usual clinical practice.

Additional provision fourth. Collegiate bodies of the Spanish Agency for Medicines and Health Products.

Within one year of the entry into force of this royal decree, the Spanish Agency for Medicines and Health Products will propose to the Ministry of Finance and Public Administration a proposal to rationalize the collegiate bodies of the subsidiary, in accordance with the provisions of Royal Decree 776/2011 of 3 June 2011, for the deletion of certain collegiate bodies and for the establishment of criteria for standardisation in the creation of collegiate bodies in the General Administration of the State and its public bodies.

Additional provision fifth. No increase in staff expenditure.

The measures included in this rule may not result in an increase in appropriations or remuneration or other personnel costs.

Additional provision sixth. Application of this royal decree to the health services of the Armed Forces.

As long as the forecasts contained in the second provision of the recast text of the Law on guarantees and the rational use of medicines and medical devices are not developed, in the application of this royal decree to the Health services of the Armed Forces shall be observed:

a) Corresponding to the Ministry of Health, Social Services and Equality, accreditation as CEIm of the Armed Forces health services.

b) The Ministry of Defense, through the General Inspection of Defense Health, will exercise the powers in matters of inspection, reception of communications and notifications and the others that this royal decree attributes to the Autonomous communities, in their field of competence.

Additional provision seventh. Adoption of development instructions.

The Spanish Agency for Medicines and Health Products is empowered to adopt the standards of good clinical practice and the instructions for the conduct of clinical trials in Spain, which will keep updated in its web page.

First transient disposition. Transitional regime regarding the evaluation of clinical studies with medicinal products or medical devices of the Ethical Committees of Clinical Research.

During the two years following the entry into force of this royal decree, the Ethical Committees of Clinical Research already accredited to the entry into force of this standard will assume the functions of the Ethics Committees of the Research on medicinal products related to the evaluation of clinical studies with medicinal products or medical devices and shall be monitored and coordinated in the same way as these functions.

Second transient disposition. Procedure for applications for authorisation and modification of clinical trials, communications and notifications prior to the full functionality of the EU portal and the EU database.

1. Until the date of full application of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 in accordance with the provisions of Article 99 of Regulation (EU) No 536/2014, the submission of applications and communications and the receipt of notifications, referred to in Articles 21.1, 26.3, 30.1, 51.2, 51.4 and 53.3 of this royal decree, shall be in accordance with the following paragraphs taking into account the provisions of Article 46 (3) and (4):

(a) Applications for authorisation and opinion of the clinical trial, as well as all subsequent communications, shall be submitted by the sponsor only via electronic means and simultaneously to the Spanish Agency of Medicines and Health Products and CEIm which accepts the evaluation on a proposal from the promoter, as provided for in article 27.6 of Law 11/2007, of 22 June, of electronic access of citizens to Public Services, except that It is justified that the access and availability of the precise technological means is not guaranteed. In any event, if this simultaneous submission does not occur, the date of the final application shall be taken into consideration for the purposes of processing the procedure.

b) To carry out the sending by electronic means is enabled the Portal of Clinical Trials with medicines of the Ministry of Health, Social Services and Equality, which can be accessed in the electronic headquarters of the Spanish Agency for Medicines and Health Products.

Alternatively, the telematic transmission without a recognized digital certificate can be carried out by presenting in the register of the Spanish Agency for Medicines and Health Products or CEIm, as appropriate, the supporting document of the Signed telematic sent in a handwritten form.

(c) The notifications of the Spanish Agency for Medicinal Products and Health Products to the promoter shall be made electronically. To this end, the sponsor must appear at the electronic headquarters of the Spanish Agency for Medicines and Health Products. The CEIm shall also make its notifications by e-mail.

d) To carry out the sending by electronic means and receive electronic notifications, the promoters must have a computer equipment, Internet connection and recognized digital certificate issued by some of the Those who are registered in the registry of the Secretariat of State of Telecommunications and the Information Society in accordance with Article 30 of Law 59/2003 of 19 December, electronic signatures. In addition, in order to receive electronic notifications, the promoters must have an email account and have expressed their consent when submitting the application.

e) Where a promoter, due to lack of resources, is unable to make a notification of suspected serious and unexpected adverse reaction to the Eudravigilance_CTM database, it may notify the Spanish Medicines Agency and Medical devices following the procedure laid down in the instructions for the conduct of clinical trials in Spain published by that Agency.

2. In line with the provisions of Article 98 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, the sponsor may, during the year following the date of full application of the said Regulation, opt for: request the authorisation of a clinical trial in accordance with Article 21.1 of this royal decree or in the manner indicated in the previous paragraph. In the latter case, subsequent notifications concerning the test shall continue to be made in accordance with the provisions of this provision up to three years after the date of full application of the said Regulation (EU).

Transitional provision third. Procedure for the authorisation of a clinical trial before the full functionality of the EU portal and the EU database.

Until the date of full application of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, in accordance with the provisions of Article 99 thereof, the procedure for the authorisation of a clinical trial, regulated in Articles 21 to 30 of this royal decree, must conform to the following rules:

(a) For the validation of an application, the sponsor shall submit an application containing all the necessary documents in respect of Part I and Part II. In the case of clinical trials with a medicinal product not authorised in any country of the European Economic Area containing an active substance or a combination of active substances not authorised in Spain, it shall request the qualification of the product at stage clinical research for that medicinal product.

The Spanish Agency for Medicinal Products and Sanitary Products and CEIm shall notify the sponsor if the application in Part I and Part II, respectively, are complete within the maximum period of ten calendar days. If any of the parties are incomplete, they shall be notified to the sponsor by setting a maximum period of 10 calendar days for the sponsor to submit their comments. This period shall be extended to 30 calendar days in the case of clinical trials that comply with the definition of 'Non-commercial clinical research'.

If the sponsor does not reply within the indicated time limit, it shall be deemed to have withdrawn from its application, and notify it accordingly. If the sponsor presents additional documentation to enable the application to be completed, the CEIm or the Agency shall, as appropriate, inform the sponsor within five calendar days of the assessment schedule, which shall start from the date of the application. the day following the date of receipt of such documentation, which shall, for the purposes of this Article, be deemed to be a valid application date.

(b) In relation to Part I of the assessment report, as regulated in Article 23 of this royal decree, the Spanish Agency for Medicines and Health Products will be responsible for sending to the promoter the conclusions of Part I of the assessment report, integrating those aspects which have been assessed by the CEIm within the time limits referred to in Article 6 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014. However, the assessment period shall be counted from the date of the valid application.

(c) In respect of Part II of the assessment report, as regulated in Article 24, it should be noted that the assessment period shall be counted from the valid date of application.

(d) Concerning the resolution of authorisation, as referred to in Article 25, the head of the Directorate of the Spanish Agency for Medicinal Products and Sanitary Products, within five days of the last date of notification to the sponsor of the findings in Part I or Part II, shall give a decision authorising the clinical trial, authorising it with conditions or refusing its authorisation.

e) A clinical trial may not be initiated without prior written authorisation from the Spanish Agency for Medicines and Health Products in the following cases:

1. clinical trials in which the Agency has notified the sponsor of objections within the period of 45 days referred to in Article 6 of Regulation (EU) No 536/2014 of the European Parliament and of the Council, of 16 April 2014.

2. Clinical trials with drugs that require the qualification of a product in clinical research phase.

3. Clinical trials with advanced therapy medicinal products, as well as clinical trials with medicinal products containing genetically modified organisms.

In these cases, after the five-day period provided for in paragraph (d) is not notified to the data subject, the request may be understood to be dismissed.

For the authorisation of subsequent clinical trials with an investigational medicinal product previously qualified as a product at the clinical investigation stage, the documentation referred to in the Annex should be updated as necessary. Article 22.1.

(f) In relation to the modification of the conditions for the authorisation of clinical trials, as referred to in Article 26, it shall be taken into account that the assessment period shall be counted from the valid date of application.

(g) Finally, and in relation to the application of Article 30, it shall be taken into account that, irrespective of the outcome of the clinical trial, the sponsor shall, within one year of the end of the clinical trial, send the Agency to the Agency. Spain for Medicines and Health Products and CEIm the summary of the test results as set out in the European guidelines in force.

Single repeal provision. Regulatory repeal.

As many provisions of the same or lower rank are repealed, they oppose the provisions of this royal decree and, in particular, the Royal Decree 223/2004 of 6 February, which regulates clinical trials with medicinal products, as well as Order SCO/256/2007 of 5 February laying down detailed principles and guidelines of good clinical practice and the requirements for authorising the manufacture or import of medicinal products for human use research.

Final disposition first. Amendment of the Statute of the Spanish Agency for Medicines and Health Products approved by Royal Decree 1275/2011 of 16 September 2011 establishing the State Agency for the Spanish Agency for Medicinal Products and Sanitary Products their Staff Regulations.

A new article is added to the Statute of the Spanish Agency for Medicines and Health Products approved by Royal Decree 1275/2011 of 16 September 2011 establishing the Spanish Agency for Medicines and Sanitary Products and its Statute is approved, in the following wording:

" Article 28a. The Health Products Committee.

1. The Committee for Health Products is the collegiate body for technical, scientific and clinical advice on safety, efficacy and quality of medical devices in all procedures developed by the Spanish Agency Medicinal products and Sanitary products, both as competent authority and as notified body.

2. They are the functions of the Healthcare Products Committee:

(a) Propose to the Spanish Agency for Medicines and Health Products the carrying out of studies and research that it deems necessary in relation to medical devices.

b) Advising the Spanish Agency for Medicines and Health Products in the aspects related to safety, clinical efficacy, operation, quality, information and the correct use of the products health.

c) Advise the Spanish Agency for Medicines and Health Products in the exercise of the function of evaluation of the adverse incidents that it is responsible for in the framework of the System of Surveillance of Sanitary Products, as in the assessment of the risks to be presented by the marketed medical devices.

d) Provide technical advice to the Spanish representatives in the working groups and meetings on health products to be held in the European Union and other international bodies.

e) Report on test methods and technical standards.

f) Advising about measures to be taken to safeguard public health and the protection of patients and users in the field of medical devices, as well as the recommendations to be issued for protection the health of the population, the safe use of the products and the monitoring and treatment of patients.

g) Issue report at the request of the Directorate of the Spanish Agency for Medicines and Health Products, in the "CE" certification procedures for medical devices.

(h) Report on any other issue in the field of medical devices.

3. The Healthcare Products Committee shall be composed of the following vowels:

a) Five vowels due to their position:

1. The head of the Directorate of the Spanish Agency for Medicines and Health Products or a person to whom you delegate.

2. The person holding the head of the Health Products Department of the Spanish Agency for Medicines and Health Products.

3. The person responsible for the Area of Surveillance and Market Control of the Department of Health Products of the Spanish Agency for Medicines and Health Products.

4. The person responsible for the certification area of the Spanish Agency for Medicines and Health Products.

5. º The person who chairs the Technical Inspection Committee.

b) Four vowels representing:

1. The Ministry of Health, Social Services and Equality.

2. The Carlos III Health Institute, on the proposal of its highest management body.

3. The National Institute of Toxicology and Forensic Sciences, at the proposal of its highest management body.

4. The Higher Council of Scientific Research, at the proposal of its highest management body.

4. Pursuant to Article 29.3, the Committee may require the collaboration of any experts deemed appropriate.

5. He shall act as President of the Head of the Directorate of the Spanish Agency for Medicines and Health Products, or person to whom he is appointed as a substitute, and as Secretary one of the members of the Spanish Medicines Agency and Sanitary Products. In the case of vacancy, absence or illness, the Chair of the Committee shall be the person holding the head of the Department of Health Products of the Spanish Agency for Medicines and Health Products.

6. The Health Products Committee shall carry out the meetings which its advisory functions require, in response to the needs of the Spanish Agency for Medicines and Health Products, operating in plenary or in commissions in accordance with the rules to establish your Rules of Procedure.

You will also be able to hold your meetings remotely and issue the reports and take decisions by written procedure, without having to resort to the face-to-face meeting of your members. "

Final disposition second. Competence title.

This royal decree is dictated by the provisions of article 149.1.16. of the Spanish Constitution, which attributes to the State exclusive competence in the field of legislation on pharmaceutical products.

Final disposition third. Faculty of development.

The head of the Ministry of Health, Social Services and Equality is empowered to make the necessary provisions for the development of this royal decree, as well as to update its annex, in accordance with the progress of the scientific and technical knowledge and in accordance with the guidelines of the European Union. In particular, the holder of the Ministry of Health, Social Services and Equality shall be empowered to review the limits laid down in Article 10.3.

Final disposition fourth. Entry into force.

This royal decree shall enter into force on the twentieth day following that of its publication in the "Official Gazette of the State", with the exception of Article 21 (1), Article 22 (1) and (3) and Article 25 (1). which shall enter into force on the date on which Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 is fully applicable in accordance with Article 99 of Regulation (EU) No 536/2014.

Given in Madrid, 4 December 2015.

FELIPE R.

The Minister of Health, Social Services and Equality,

ALFONSO ALONSO ARANEGUI

ANNEX

Data that will include the REEC

1. The identification number of the study in the primary registry.

2. Date of registration in the REEC.

3. Secondary identification numbers.

4. Brief summary with justification for the conduct of the study.

5. Source of funding or material support.

6. Promoter.

7. Contact for general public inquiries.

8. Contact for scientific consultations.

9. Public title of the study.

10. Scientific title of the study and acronym, if the study had it.

11. Countries where recruiting participants are expected to be recruited.

12. Test centres.

13. Disease or health problem object of study.

14. Interventions being investigated.

15. Main criteria for inclusion and exclusion.

16. Type and scope of the study.

17. Date of recruitment of the first participant in Spain.

18. Sample size (number of subjects to include).

19. Study status (not started; recruitment started; recruitment completed, interrupted or temporarily suspended; completed in Spain; completed in all participating countries).

20. Objective and main variables and times when the assessment is to be performed.

21. Objectives and secondary variables of the study and moments in which the assessment is to be carried out.

22. Date of the opinion of the CEIm and of the authorisation by the Spanish Agency for Medicines and Health Products or by the relevant autonomous community (where applicable).

23. Study portal (if applicable).

24. Results of the study (the registry will contain a link to the scientific publications of the study. The presentation of the results shall, where appropriate, be adjusted to the European Union

.

25. Date of the last modification of the record in the REEC.