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Royal Decree 223/2004 Of 6 February, Which Regulates Clinical Trials With Medicines.

Original Language Title: Real Decreto 223/2004, de 6 de febrero, por el que se regulan los ensayos clĂ­nicos con medicamentos.

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TEXT

Clinical trials with medicinal products have been subject to regulation in Title III of Law 25/1990 of 20 December of the Medicamento and its regulatory development in this field by means of Royal Decree 561/1993, of 16 of April, establishing the requirements for the conduct of clinical trials with medicinal products.

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 relating to the application of good clinical practices in the conduct of clinical trials of medicinal products for human use, has come to harmonise the laws of the Member States of the European Union on clinical trials with medicinal products in human beings, which has made it necessary the modification of the Spanish legislation in force in this field. In this regard, Article 125 of Law 53/2002 of 30 December 2002 on fiscal, administrative and social measures has introduced a number of amendments to Title III of Law 25/1990 of 20 December 1990 on the the purpose of eliminating the discrepancies in that standard with Directive 2001 /20/EC, thus providing the necessary legal cover for this regulation. It has also been taken into account in the elaboration of the provisions of Law 41/2002, of 14 November, basic regulation of the autonomy of the patient and of rights and obligations regarding information and clinical documentation.

This royal decree, therefore, comes to incorporate in its entirety the internal legal order Directive 2001 /20/EC, and replaces the current Royal Decree 561/1993, of 16 April, establishing the requirements for the conduct of clinical trials with medicinal products, giving new regulatory development to Law 25/1990, of 20 December, of the Medicamento, in terms of clinical trials.

In this royal decree, the basic principles for the conduct of clinical trials with human beings based on the protection of human rights and the dignity of the human being have been taken into account. of biology and medicine, reflected in the Declaration of Helsinki and the Oviedo Convention on Human Rights and Biomedicine, as well as the rules for the proper protection of personal data.

On the other hand, new administrative procedures are being provided for the authorization of the clinical trials by the General Administration of the State, which means speeding up and simplifying the procedures currently in place. existing, bringing together the various regulations in this field from the Member States of the European Union and allowing mutual recognition between the health authorities of those States in respect of the results of clinical trials performed.

As regards the evaluation of the clinical trial, in the field concerned, by the Ethical Committee of Clinical Research, in addition to the setting of maximum deadlines for this evaluation, the opinion is required. only. In this sense, in the multicenter clinical trials, involving two or more centers located in Spain, a reference committee will be appointed among the various ethical committees involved in the issuance of the said single opinion, which calls for the creation of a coordinating body called the Coordinating Centre for Ethical Committees of Clinical Research.

Special mention deserves the obligation to apply the norms of good clinical practice to the planning, realization, registration and communication of all clinical trials that are carried out in Spain, as a set of ethical requirements and quality scientists recognised at international level and as a guarantee of the protection of the rights, safety and well-being of the test subjects, as well as the reliability of their results.

The verification of compliance with good clinical practice standards and inspection of data, information and documents to check that they have been produced, recorded and communicated correctly, as well as the compliance with the rules of correct manufacture in the manufacture, import and labelling of investigational medicinal products, the monitoring of the safety of these medicinal products and the communications between the competent authorities in the field, have also been collected and taken into account as essential requirements for justify the involvement of human beings in clinical trials.

Finally, they complement this royal decree the norms of good clinical practice and the instructions for the conduct of clinical trials in Spain, or in their case, the guidelines of the European Commission, which will be published by the Ministry of Health and Consumer Affairs.

This royal decree by which Directive 2001 /20/EC is incorporated into the internal legal order is developed under Title III of Law 25/1990 of 20 December of the Medicament and is issued under the provisions of the Article 149.1.16. of the Spanish Constitution, in accordance with article 2.1 of that law.

In the elaboration of this royal decree, the autonomous communities and affected sectors have been heard.

In its virtue, on the proposal of the Minister of Health and Consumer Affairs, with the prior approval of the Minister of Public Administrations, in agreement with the State Council and after deliberation by the Council of Ministers at its meeting of the day 6 February 2004,

D I S P O N G O:

CHAPTER I

General provisions

Article 1. Scope of application.

1. This royal decree will apply to clinical trials with medicinal products for human use in Spain.

For these purposes, the administration of an investigational medicinal product to a single patient, in the field of usual medical practice and for the sole purpose of achieving a benefit, will not be considered a clinical trial. therapeutic for the patient, which shall be governed by the provisions on compassionate use in Article 28.

The medical practice and professional freedom of prescription of the physician shall in no case cover the conduct of unauthorised clinical trials or the use of secret or undeclared remedies to the health authority.

2. The observational studies, as defined in Article 2 (c), which shall be governed by their specific rules, are excluded from the scope of this royal decree.

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

Article 2. Definitions.

For the purposes of this royal decree, the following definitions apply:

(a) Clinical study: any research carried out in humans to determine or confirm the clinical, pharmacological and/or other pharmacodynamic effects, and/or to detect adverse reactions, and/or to study the absorption, distribution, metabolism and excretion of one or more investigational medicinal products in order to determine their safety and/or their efficacy.

For these purposes, the definition of investigational medicinal product as provided for in paragraph (d) shall apply.

b) A multicenter clinical trial: a clinical trial conducted according to a single protocol but in more than one center and, therefore, performed by more than one investigator.

c) Observational study: A study in which medicinal products are prescribed in the usual manner, in accordance with the normal conditions of clinical practice (those established in the marketing authorisation). The assignment of a patient to a particular therapeutic strategy will not be decided in advance by a test protocol, but will be determined by the usual practice of the medicine, and the decision to prescribe a given drug be clearly dissociated from the decision to include the patient in the study. No intervention will be applied to patients, either diagnostic or follow-up, other than the usual clinical practice, and epidemiological methods will be used for the analysis of the data collected.

(d) investigational medicinal product: a pharmaceutical form of an active substance or placebo that is investigated or used as a reference in a clinical trial, including products with a marketing authorisation when used or combine (in the formulation or in the packaging) differently than the authorised one, or when used to treat an unauthorised indication, or for more information on an authorised use.

e) Promoter: individual, company, institution or organisation responsible for the initiation, management and/or funding of a clinical trial.

f) Monitor: trained professional with the necessary clinical 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.

g) Contract Research Organization (CRO): a natural or legal person engaged by the promoter to perform the promoter's duties or duties in relation to the clinical trial.

h) Investigator: a doctor or a person who has a recognised profession to carry out research on the basis of his or her scientific background and experience in the required health care. The investigator is responsible for conducting the clinical trial at a center. If it is a team that performs the test at a center, the investigator is responsible for the team and can be called a principal investigator.

i) Coordinator investigator: investigator responsible for the coordination of researchers from all Spanish centers participating in a multicenter clinical trial.

j) A researcher's manual: a set of clinical and non-clinical data on the investigational medicinal product relevant to the study of this medicinal product in humans.

k) Protocol: a document describing the objectives, design, methodology, statistical considerations and organisation of an essay. The term protocol refers to the original protocol, its successive versions and its modifications.

l) Test subject: individual involved in a clinical trial, either receiving the investigational medicinal product or as a control.

m) Informed consent: decision, which must be written and dated and signed, to participate in a clinical trial voluntarily adopted by a person who is able to give his consent after having been duly informed and documented about their nature, importance, implications and risks.

In the event that the subject has an impediment to write, consent may be granted in exceptional cases orally in the presence of at least one witness.

Where the subject of the test is not a capable person to give his consent, the decision shall be taken by his legal representative in accordance with the terms of Article 7.

n) Ethical Committee for Clinical Research (CEIC): an independent body, made up of healthcare professionals and non-healthcare members, in charge of ensuring the protection of the rights, safety and welfare of the subjects participate in a trial and provide a public guarantee in this respect, by means of an opinion on the test protocol, the suitability of the investigators and the adequacy of the facilities, as well as the methods and documents to be used to inform the subjects of the test in order to obtain their informed consent. In the case of multicenter clinical trials, the Clinical Research Committee responsible for issuing the opinion is called the Ethical Committee for Clinical Research of Reference.

n) Inspection: official review by a competent authority of the documents, facilities, files, quality assurance systems and any other elements that the competent authority considers related to the clinical trial and which can be found at the site of the test, at the premises of the sponsor and/or the contract research organisation, or in any other establishment which the competent authority considers appropriate to inspect.

o) Adverse event: any adverse health incidence in a patient or clinical trial subject treated with a medicinal product, even if it does not necessarily have a causal relationship to such treatment.

p) Adverse reaction: any harmful and unintended reactions to an investigational medicinal product, regardless of the dose administered.

q) Serious adverse event or serious adverse reaction: any adverse event or adverse reaction that, at any dose, produces death, threatens the life of the subject, makes hospitalization or prolongation necessary of this, produce permanent or significant disability or disability, or result in a congenital anomaly or malformation. For the purposes of their notification, any suspected adverse event or adverse reaction that is considered to be a medical point of view, even if they do not meet the above criteria, shall also be treated as serious.

r) Unexpected adverse reaction: adverse reaction whose nature or severity does not correspond to the information concerning the product (e.g. the investigator's manual in the case of an unauthorised investigational medicinal product) for the placing on the market, or the product fiche of the product in the case of an authorised medicinal product).

CHAPTER II

Protection of test subjects

Article 3. Ethical postulates.

1. A clinical trial may only be initiated when the appropriate Clinical Research Ethics Committee and the Spanish Agency for Medicinal Products and Sanitary Products have considered that the expected benefits for the test subject and for the The company may also continue to continue to monitor compliance with this criterion on a permanent basis.

2. Clinical trials will be conducted in conditions of respect for the rights of the subject and the ethical postulates that affect biomedical research with human beings. In particular, the physical and mental integrity of the subject, as well as the privacy and protection of his data, must be safeguarded in accordance with the Organic Law 15/1999 of 13 December on the Protection of Personal Data. The informed consent of each of the subjects of the test, freely expressed, shall be obtained and documented prior to their inclusion in the test in the terms provided for in Article 7 of this royal decree.

3. Clinical trials may only be performed when all of the following requirements are met:

(a) Dispose of sufficient scientific data and, in particular, pharmacological and toxicological tests on animals, ensuring that the risks involved in the person in which it is carried out are admissible.

b) That the study is based on the available knowledge, the information sought, presumably, an advance in scientific knowledge about the human being or to improve its health status and its design minimises the risks for the subjects participating in the.

(c) The foreseeable risks and disadvantages for the test subjects have been weighted with respect to the foreseeable benefits for each subject of the trial and future patients.

4. In order to ensure optimal protection of the health and rights of the subjects, no obsolete or repetitive investigations may be carried out.

5. The clinical trial should be designed to minimise pain, discomfort, fear and any other foreseeable risks in relation to the disease and age or degree of development of the subject; both the risk threshold and the degree of risk. discomfort should be defined specifically and monitored during the test, especially when the test subjects are minor, adult unable or constitute a particularly vulnerable population due to their economic situation, medical or social.

6. The treatment, communication and transfer of the personal data of the subjects participating in the trial shall be in accordance with the provisions of the Organic Law 15/1999 of 13 December on the Protection of Personal Data, and shall include: expressly in the informed consent.

7. The health care that is distributed and the medical decisions to be taken on the subjects will be the responsibility of a qualified doctor or dentist.

8. The participants in clinical trials without direct potential benefit to the research subject will receive compensation from the promoter for the inconvenience suffered. The amount of the economic compensation shall be in relation to the characteristics of the test, but in no case shall it be so high as to induce a subject to participate for reasons other than interest in scientific advancement.

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

In the extraordinary cases of investigations without direct potential benefit for the subject under investigation in minors and unable, to avoid the possible exploitation of these subjects, no economic compensation will be produced by the sponsor, with the exception of the drawback of the extraordinary expenses and productivity losses resulting from the participation of the subject in the test.

9. Subjects participating in trials with a possible direct potential benefit to the research subject or their legal representatives may only receive from the sponsor the reimbursement of extraordinary expenses and lost productivity. which are derived from their participation in the test.

10. The test subjects shall have a point where they can obtain more information on the test, which shall be included in the information sheet for the subject.

Article 4. From clinical trials with minors.

Without prejudice to the application of the general provisions set out in the previous article, only minor clinical trials may be carried out when the following special conditions are met:

(a) that the tests are of specific interest to the population under investigation, and only where such research is essential to validate data from clinical trials carried out on persons capable of giving their informed consent or obtained by other means of investigation. In addition, the investigation must be directly related to any disease that the child suffers from or to be of a nature that can only be performed on minors.

b) That the welfare of the subject always prevails over the interests of science and society, and there is data to provide that the expected benefits outweigh the risks or that the risk associated with the test is minimum.

c) That obtaining the informed consent is in accordance with the article. 7.3.

d) That the protocol be approved by an Ethics Committee of Clinical Research that has experts in pediatrics or has sought advice on clinical, ethical and psychosocial issues in the field of pediatrics.

e) To follow the relevant scientific guidelines of the European Agency for the Evaluation of Medicinal Products.

Article 5. From clinical trials with disabled adults.

Without prejudice to the application of the general provisions laid down in Article 3, clinical trials may only be carried out in adults who are not in a position to give their informed consent and who have not prior to the beginning of their incapacity, when the following special conditions are also met:

(a) that the tests are of specific interest to the population under investigation, and such research is essential for validating data from clinical trials carried out in persons capable of giving their consent; reported or obtained by other means of investigation. In addition, the research should be directly related to any disease that the adult is suffering from, and that is weakened or life-threatening.

(b) That the welfare of the subject prevails over the interests of science and society, and there is data to provide for the provision of any benefit to the patient who prevails over the risks or does not produce any risk.

c) That the informed consent is in accordance with the provisions of Article 7.3. In any case, the subjects should not have refused to give their informed consent before the beginning of their incapacity.

d) That the protocol be approved by an Ethics Committee of Clinical Research that has experts in the disease in question or has sought advice from such experts on clinical, ethical and psychosocial in the field of disease and the group of affected patients.

Article 6. From clinical trials without direct benefit to the health of the subjects.

1. In clinical trials with no direct potential benefit to the health of the participants, the risk that these subjects will assume will be justified by the expected benefit to the community.

2. In minors and disabled subjects, trials may be conducted without direct direct benefit to the subject only if, in addition to taking into account the provisions of Articles 4 and 5, the Ethical Committee of Clinical Research considers that meet the following requirements:

a) That the necessary measures are taken to ensure that the risk is minimal.

b) That the interventions to which the subjects of the test are to be submitted are comparable to those that correspond to the usual medical practice according to their medical, psychological or social situation.

c) That the test may obtain relevant knowledge about the disease or situation under investigation, which is of vital importance for understanding, palliating or curing it.

d) That this knowledge cannot be otherwise obtained.

e) That there are guarantees on the correct obtaining of informed consent, as referred to in Article 7.

3. In pregnant or breast-feeding women, clinical trials may only be conducted with no direct potential benefit to them when the Ethical Committee for Clinical Research concludes that they do not pose a foreseeable risk to their health or to the the fetus or child, and that relevant and relevant knowledge about pregnancy or breast-feeding will be obtained.

Article 7. From informed consent.

1. The obtaining of informed consent should take into account the aspects indicated in the European recommendations in this respect and which are included in the instructions for the conduct of clinical trials in Spain or, where appropriate, in the guidelines of the European Union.

2. The test subject shall give its consent after having understood, by means of a prior interview with the investigator or a member of the research team, the objectives of the test, its risks and disadvantages, as well as the the conditions under which it shall be carried out, and after having been informed of its right to withdraw from the test at any time without causing any injury to it.

The consent will be documented through a sheet of information for the subject and the consent document. The information sheet shall contain only relevant information, expressed in clear and comprehensible terms for the subjects, and shall be in the subject's own language.

3. Where the subject of the test is not a capable person to give his or her consent or is not in a position to do so, the decision shall be taken, taking into account the provisions of this Article.

a) If the subject of the test is minor:

1. The prior informed consent of the parents or the legal representative of the child shall be obtained; the consent shall reflect the presumed will of the child and may be withdrawn at any time without prejudice to him. Where the child is 12 years of age or older, he/she must also give his/her consent to participate in the trial.

2. The youngest will receive, from staff who have experience in dealing with minors, an information about the trial, risks and benefits appropriate to their ability to understand.

3. The investigator will accept the child's explicit desire to refuse to participate in the trial or to withdraw at any time, when he or she is able to form an opinion based on the information received.

4. The promoter shall inform the Prosecutor's Office of the authorizations of the clinical trials whose population includes minors.

b) If the subject is an adult with no ability to grant their informed consent:

1. The informed consent of your legal representative must be obtained, after having been informed about the possible risks, discomforts and benefits of the trial. Consent shall reflect the presumed will of the subject and may be withdrawn at any time without prejudice to the subject.

2. When the conditions of the subject permit, the subject must also give his consent to participate in the test, after having received all the relevant information adapted to his level of understanding. In this case, the investigator shall take into account the will of the person unable to withdraw from the test.

4. Where the clinical trial has a specific interest for the population in which the investigation is carried out and the reasons for the need for the administration of the investigational medicinal product are warranted, it may be subject to a clinical trial without obtain prior consent in the following cases:

(a) If there is an immediate serious risk to the physical or mental integrity of the subject, there is no appropriate therapeutic alternative in clinical practice and it is not possible to obtain their consent or that of their legal representative. In this case, whenever circumstances permit, persons linked to it will be consulted in advance for family reasons or in fact.

b) If the subject is unable to make decisions due to his physical or mental state and lacks legal representative. In this case, consent will be provided by people linked to it for family reasons or in fact.

In both cases, this eventuality and the manner in which it will proceed should be found in the documentation of the study approved by the Ethical Committee of Clinical Research, and the subject or his legal representative will be informed as soon as possible. it is possible and must give its consent to continue in the test if it were to proceed.

5. The subject participant in a clinical trial, or his legal representative, may revoke his or her consent at any time, without the expression of cause and without thereby deriving responsibility or prejudice to the participating subject.

Article 8. Insurance or other financial collateral of the test subjects.

1. A clinical trial with investigational medicinal products may only be carried out if, in advance, a insurance or other financial guarantee has been concluded covering the damages which may result from the test for the person in which the it should be carried out, unless the test relates only to medicinal products authorised in Spain, its use in the test is in accordance with the authorised conditions of use and the Ethical Committee for Clinical Research considers that the the subjects to be subjected to their participation in the test pose an equivalent risk or less than the one that would correspond to your attention in the usual clinical practice.

2. The sponsor of the trial is responsible for the procurement of such liability insurance or financial collateral and they shall cover the responsibilities of the sponsor, principal investigator and his/her collaborators, and of the hospital or centre where the clinical trial is carried out.

3. In the case provided for at the end of paragraph 1 of this Article, where no insurance or other financial guarantee is made or, for all circumstances, the insurance or the financial guarantee provided for does not cover the damage, the promoter of the clinical trial, the principal investigator and the hospital or centre where the test is performed shall be jointly and severally liable, without the need for any fault, of the damage to the health of the subject under the clinical trial, as well as of the the economic damage caused by the burden of proof that they are not the result of the test clinical or therapeutic or diagnostic measures to be taken during its performance. Neither the administrative authorisation nor the favourable opinion of the Ethics Committee for Clinical Research shall exempt the sponsor from the clinical trial, the principal investigator and his collaborators or the hospital or centre where the clinical trial is conducted. clinical trial in these circumstances.

4. 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 termination 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.

5. 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 subject subject to the clinical trial shall be liable to compensation, as well as 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 is included within the adverse reactions proper to the medication prescribed for such pathology, as well as the evolution of its own disease as a result of the ineffectiveness of treatment.

6. The minimum amount of liability to be guaranteed shall be EUR 250,000 per subject subject to clinical trial, as a lump sum allowance. Where the compensation is fixed as a constant or increasing annual income, the limit for the insurance cover or the financial guarantee shall be at least EUR 25 000 per year for each subject submitted to the clinical trial, maximum insured capital or as the maximum amount of the financial guarantee an sublimit per clinical trial and year of 2,500,000 euro.

The Ministry of Health and Consumer is authorised to review the limits set out above.

7. Where the sponsor and principal investigator are the same person and the clinical trial is carried out in a health facility under 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.

CHAPTER III

From the Ethical Committees of Clinical Research

Article 9. From the Coordinating Center of the Ethical Committees of Clinical Research.

1. In order to facilitate the single opinion, the Coordinating Centre for Clinical Research Committees will be set up. This organization is constituted as the operational technical unit that aims to make it easier for the Ethical Research Committee accredited by the Autonomous Communities to share quality standards and evaluation criteria. appropriate and homogeneous and to foster agility in the process of obtaining the single opinion.

2. The Coordinating Centre of Ethical Committees of Clinical Research is attached to the Ministry of Health and Consumer Affairs, through the General Secretariat of Health.

3. The Coordinating Center of the Ethical Committees of Clinical Research will collaborate with the competent authorities of the autonomous communities and will render accounts of their activity in the Interterritorial Council of the National Health System.

4. The Coordinating Center of Ethical Research Committees will develop the following activities:

(a) Facilitate the single opinion in multi-stage trials.

b) Coordinate with the Autonomous Communities the development of a computer system of communication between Ethical Committees of Clinical Research.

c) Manage the clinical trial database of the national network of Ethical Clinical Research Committees.

d) Promote common assessment criteria in the Ethical Committees of Clinical Research.

e) Promote the formation of members of the Ethical Research Committees.

f) Promote discussion forums among Ethical Research Committees.

g) Act as a point of contact to provide information on the functioning of the national network of Ethical Clinical Research Committees.

h) Provide advice to the Ethical Research Committees on procedural issues.

i) Develop the annual activity memory.

Article 10. Functions of the Ethical Committees of Clinical Research.

The Clinical Research Ethics Committees will perform the following functions:

(a) Evaluate the methodological, ethical and legal aspects of the clinical trials referred to them in accordance with the provisions of Section 2 of Chapter IV.

b) Evaluate the relevant modifications of the licensed clinical trials.

c) Track the test, from its beginning to the receipt of the final report.

Article 11. Accreditation of the Ethical Committees of Clinical Research.

The Ethical Committees of Clinical Research will be accredited by the competent health authority in each autonomous community, who will determine the geographical and institutional scope of each committee. Such accreditation shall be renewed periodically by that health authority in accordance with the procedures and time limits laid down by that authority. Both the initial accreditation and its renewals must be notified to the Spanish Agency for Medicines and Health Products and to the Coordinating Center of Ethical Committees of Clinical Research.

Article 12. Composition of the Ethical Committees of Clinical Research.

1. The Ethics Committee of Clinical Research must be composed of at least nine members, so as to ensure the independence of its decisions, as well as its competence and experience in relation to the methodological, ethical and legal aspects research, pharmacology and clinical care practice in hospital and extra-hospital medicine.

2. Among the members of the aforementioned committee will be doctors, one of whom will be a clinical pharmacologist, a hospital pharmacist, and a university graduate in Nursing.

At least one member must be independent of the centers in which research projects are carried out that require the ethics evaluation by the committee.

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

3. A member renewal system will be guaranteed to allow for new additions on a regular basis, while maintaining the experience of the committee.

4. As provided for in Article 4 of Law 25/1990 of 20 December 1990, the membership of an Ethics Committee for Clinical Investigation shall be incompatible with any class of interests arising from the manufacture and sale of medicinal products and medical devices.

Article 13. Minimum requirements regarding the means and infrastructure of the Ethical Committees of Clinical Research.

Health authorities in the corresponding Autonomous Communities will ensure that each Committee

Accredited Clinical Research Ethics count at least with the following means:

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

b) Computer equipment with sufficient capacity to handle all the information generated by the committee and the availability of a rapid information transmission system.

(c) Administrative and technical staff to enable the committee to properly exercise its functions.

Article 14. General rules of operation of the Ethical Committees of Clinical Research.

1. Neither the Ethics Committee for Clinical Research nor any of its members may directly or indirectly receive any remuneration from the sponsor of the trial.

2. The Ethics Committee for Clinical Research shall draw up and follow for its operation standard working procedures which at least refer to:

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

b) The frequency of meetings, which at least must be monthly.

c) The procedure to summon its members.

d) Administrative aspects, including documentation to be presented.

e) Cases where a rapid review of the documentation for a clinical trial and the procedure to be followed in these cases can be performed.

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

g) Decision-making mechanisms.

h) The preparation and approval of meeting minutes.

i) The archiving and preservation of the committee's documentation and related clinical trials.

3. In cases where there is a Commission of Inquiry or an Assistant Ethics Committee, a member of each committee shall be a member of the committee.

4. Where the Ethics Committee for Clinical Research does not gather the knowledge and experience necessary to evaluate a particular clinical trial, it shall seek the advice of any expert non-commitee who shall respect the principle of confidentiality. This way:

(a) When the committee evaluates clinical research protocols with surgical procedures, diagnostic techniques or medical devices, it will have the advice of at least one expert in the procedure or technology. to be evaluated.

(b) Where the committee evaluates clinical trials involving minors or disabled subjects, it shall have the advice of at least one person with experience in the treatment of the population to be included in the trial.

5. The principal investigator or co-workers of a clinical trial shall not be able to participate in the assessment, or in the opinion of their own protocol, even if they are members of the committee.

6. Each meeting of the committee will be included in the corresponding minutes, detailing at least the members attending, which for each study evaluated have weighted the aspects contemplated in this royal decree and the decision adopted on each test.

CHAPTER IV

From intervention on clinical trials with drugs

Section 1. Common Provisions

Article 15. Requirements for the conduct of clinical trials.

For the conduct of clinical trials with medicinal products, it will be necessary to provide the following favorable opinion of the Ethical Committee of Clinical Research, the conformity of the address of each of the centers where the study is to be carried out and the authorisation of the Spanish Agency for Medicinal Products and Sanitary Products.

The opinion and the authorization referred to in the preceding paragraph may be requested simultaneously or not, according to the promoter's preferences.

Section 2 of the Opinion of the Ethical Committees for Clinical Research

Article 16. Procedure initiation.

1. The sponsor shall request in writing the opinion of the Ethics Committee for Clinical Research, in accordance with the instructions for the conduct of clinical trials in Spain or, where appropriate, the guidelines of the European Commission, which will publish the Ministry of Health and Consumer Affairs.

2. The application must be accompanied by the following documentation:

a) The protocol.

b) The investigator's manual.

c) Documents concerning informed consent, including the information sheet for the test subject.

d) Documents on the suitability of the researcher and their collaborators.

e) Documents on the suitability of the facilities.

(f) The amounts and the manner in which the investigators and subjects may be, where appropriate, remunerated or compensated for their participation in the clinical trial, as well as the relevant elements of any contract envisaged between the promoter and the center.

g) A copy of the insurance policy or proof of the financial guarantee of the clinical trial or a certificate from the clinical trial, where applicable.

(h) In the cases provided for in Article 8.3 of the absence of insurance or insurance with partial coverage, a signed document of liability in the event of damages produced as a result of the test shall be accompanied.

i) The procedures and material used for the recruitment of test subjects.

j) The commitment of the researchers who are expected to participate in the trial.

Article 17. Evaluation criteria for the issue of the opinion.

1. The relevant Clinical Research Ethics Committee shall evaluate the protocol, the tigator manual and the other documentation accompanying the application and shall deliver its opinion, taking into account in particular the following: issues:

(a) The relevance of the clinical trial, taking into account available knowledge.

b) The relevance of their design to obtain conclusions based on the appropriate number of subjects in relation to the objective of the study.

c) The selection and withdrawal criteria of the test subjects, as well as the fair selection of the sample.

d) The justification of the foreseeable risks and disadvantages in relation to the expected benefits for the test subjects, for other patients and for the community, taking into account the principle of protection of the subjects of the test developed in Article 3.

e) The justification of the control group (either placebo or an active treatment).

f) The forecasts for the follow up of the test.

g) The suitability of the researcher and their collaborators.

h) The suitability of the facilities.

i) The suitability of the written information for the subjects of the trial and the procedure for obtaining informed consent, and the justification of the investigation in persons unable to give their informed consent.

j) The insurance or financial guarantee provided for the test.

k) The amounts and, where appropriate, forecasts of remuneration or compensation for the researchers and subjects of the trial and the relevant aspects of any agreement between the promoter and the centre, which must be included in the contract provided for in Article 30.

l) The planned plan for the recruitment of the subjects.

2. The questions referred to in paragraphs (g), (h) and (k) of the previous paragraph shall be assessed for each of the centres involved in the clinical trial.

Article 18. Procedure for the issue of the opinion in single-entry tests.

1. In the case of single-entry clinical trials, the application shall be submitted to the relevant Clinical Research Committee. The applicant shall, within 10 calendar days, verify that the application complies with the requirements laid down in Article 16 and, without prejudice to its remedy where appropriate, shall inform the sponsor of the acceptance of the application with an indication of the the timing of the assessment or, where appropriate, its inadmissibility.

2. The Ethics Committee for Clinical Research shall have a maximum period of 60 calendar days, from the notification of the admission to the application, to communicate its reasoned opinion to the sponsor and the Spanish Medicines Agency. Sanitary Products.

3. During the period set out in the previous paragraph, the committee may request additional information from the sponsor only; in such a case, the assessment period shall be suspended until the requested information is received.

4. In the case of clinical trials referring to medicinal products for gene therapy, somatic cell therapy or containing genetically modified organisms, the time limit laid down in paragraph 2 shall be 90 calendar days. That period may be extended for a further 90 days when the opinion of an expert committee is received.

5. In the case of clinical trials referring to xenogenic cell therapy, there shall be no limitation of the time limit for the issue of the reasoned opinion.

Article 19. Single opinion in multicenter clinical trials.

1. In clinical trials involving two or more centres located in Spain, a single opinion shall be issued irrespective of the number of Clinical Research Committees involved.

The single opinion shall be adopted in accordance with the procedure laid down in the following paragraphs.

2. The sponsor shall submit the application for the evaluation of the test to the Ethics Committee for Clinical Research, which shall act as a reference committee and shall be responsible for the issuance of the single opinion and the other Research Ethics Committees. Clinical involvement.

3. The Reference Clinical Research Ethics Committee shall, within the maximum period of 10 calendar days, verify that the application meets the requirements laid down in Article 16 and, without prejudice to its remedy where appropriate, shall inform the sponsor and the Ethics Committee of Clinical Research involved in the test the admission to processing of the application with an indication of the timing of the assessment or, where appropriate, its inadmissibility.

4. The Ethics Committee for Clinical Research of Reference shall have a maximum period of 60 calendar days, from the notification of the admission to the sponsor to communicate its reasoned opinion to the promoter, to the Spanish Agency of Medicinal products and Sanitary products and the other committees involved in the trial.

Each committee involved shall submit a report on the local aspects of the test with sufficient time to the reference committee, as well as on any other aspect of the test that it considers relevant.

5. During the period provided for in the preceding paragraph, the Reference Clinical Research Ethics Committee may request additional information from the sponsor only; in such a case, the calculation of the assessment period shall be suspended until such time as receives the requested information. Such information shall also be submitted to the other committees concerned.

6. The reports of the other committees concerned must be taken into account by the Ethical Committee for Clinical Research of Reference for the issuance of the single opinion, which will be motivated, in particular, in the event of a different opinion from another. committee on any aspect of the test, but shall only bind the reference committee with respect to local aspects.

7. In the case of clinical trials referring to medicinal products for gene therapy, somatic cell therapy or containing genetically modified organisms, the time limit laid down in paragraph 4 shall be 90 calendar days. That period may be extended for a further 90 days when the opinion of an expert committee is received.

8. In the case of clinical trials referring to xenogenic cell therapy, there shall be no limitation of the time limit for the issue of the reasoned opinion.

Section 3 of the authorization of the Spanish Agency for Medicines and Health Products

Article 20. Procedure initiation.

1. The authorisation of the clinical trial shall be requested in writing from the sponsor addressed to the Director of the Spanish Agency for Medicinal Products and Sanitary Products, in accordance with the instructions for the conduct of clinical trials in Spain or, where appropriate, the guidelines of the European Commission, to be published by the Ministry of Health and Consumer Affairs.

2. The application must be accompanied by the following documentation:

a) Test protocol.

b) A researcher's manual.

c) Information sheet for test subjects.

(d) The investigational medicinal product, where applicable.

e) Accreditation of the payment of the fee provided for in Article 117.1, Group V, Section 5.2, of Law 25/1990 of 20 December of the Medication.

3. In addition, it will be necessary to qualify as a clinical research product for those investigational medicinal products which are defined in the instructions for the conduct of clinical trials in Spain or, where appropriate, the guidelines of the European Commission, to be published by the Ministry of Health and Consumer Affairs.

In order to qualify the medicinal product as a clinical research product, for the purposes set out in Article 24, the following documentation shall be provided:

a) Request form.

b) Expedient of the investigational medicinal product.

(c) Accreditation of the payment of the fee provided for in Article 117.1, Group V, Section 5.1, of Law 25/1990 of 20 December of the Medication.

Article 21. Validation of the request.

1. The Spanish Agency for Medicinal Products and Sanitary Products, within 10 calendar days, shall verify that the application meets the requirements laid down in the previous Article, and shall notify the applicant of the admission to the application with an indication of the applicable procedure, as well as the time limit for the notification of the decision.

2. Where the application does not meet the requirements set out in the previous paragraph, the applicant shall be required to remedy the deficiencies within the maximum period of 10 days, with the indication that, if he does not do so, the application shall be closed. a request for a decision which shall be made in accordance with the terms laid down in Article 42 of Law No 30/1992 of 26 November 1992, of a Legal Regime for Public Administrations and of the Common Administrative Procedure.

3. Within 10 calendar days, from the submission of the required documentation, the applicant shall be notified of the admission to the processing of his application in accordance with the terms provided for in paragraph 1 of this Article or, where appropriate, his admission to processing.

Article 22. Ordinary procedure.

1. The authorization shall be deemed to have been granted if within 60 calendar days, from the notification of the admission to the application, the Spanish Agency for Medicinal Products and Sanitary Products does not communicate reasoned objections to the applicant. provided that the favourable opinion of the Ethical Committee for Clinical Research and the conformity of the management of the centres participating in the test has been notified prior to the Spanish Agency for Medicinal Products and Sanitary Products.

2. In the event of reasoned objections, the applicant shall have a period of 15 calendar days to amend his application in accordance with the objections raised or, in the event of a discrepancy with those objections, to make the and submit any documents deemed relevant in support of your application.

After the time limit set in the previous paragraph without the applicant having modified the application or submitted claims, the applicant shall be deemed to have withdrawn its application.

3. In the light of the amendment proposed by the applicant or, where appropriate, its claims, the Spanish Agency for Medicinal Products and Sanitary Products shall issue express, authorizing or refusing the test, which shall be notified to the applicant. applicant within 15 days of entry into its general register of the written amendment or claims.

4. The authorisation of the clinical trial shall be without prejudice to the application, where appropriate, of the legislation in force on the contained use of genetically modified organisms, and the deliberate release into the environment of genetically modified organisms.

Article 23. Special procedures.

1. Without prejudice to the foregoing Article, a clinical trial may not be initiated without the prior written authorisation of the Spanish Agency for Medicinal Products and Health Products in the following cases:

(a) Clinical trials in which the Spanish Agency for Medicinal Products and Sanitary Products has communicated objections to the sponsor within the time limit set out in paragraph 1 of the previous Article.

b) Clinical trials with medicinal products that require the qualification of a clinical research product.

c) Clinical trials with gene therapy medicinal products, somatic cell therapy (including xenogenic cell therapy), as well as all medicinal products containing genetically modified organisms.

2. In the cases provided for in the preceding paragraph, the Spanish Agency for Medicinal Products and Sanitary Products shall issue an express decision authorising or refusing the clinical trial, in accordance with the procedure and time limits provided for in Article 22, with the particularities set out in paragraphs 3 and 4 below.

After the corresponding deadline has passed without the person being notified of the resolution, the request may be understood to be dismissed.

3. In clinical trials with gene therapy medicinal products, somatic cell therapy (excluding xenogenic cell therapy), as well as all medicinal products containing genetically modified organisms, the maximum time limit for authorisation The clinical trial shall be for 90 calendar days. This period shall be extended by 90 calendar days where it is necessary to obtain a report in accordance with the rules in force.

4. In clinical trials with xenogenic cell therapy medicinal products, the Spanish Agency for Medicinal Products and Sanitary Products shall have no time limit for the communication of objections or for the authorisation or refusal of the test.

Article 24. Products in clinical research phase.

1. The Spanish Agency for Medicinal Products and Sanitary Products, where it authorizes a clinical trial with an investigational medicinal product, shall record in the approval of the test the qualification of the said medi as a product in the research phase. clinical, in the cases where appropriate.

2. The Spanish Agency for Medicines and Health Products will keep an updated register of investigational medicinal products qualified as products in the clinical research phase, listing the specific indications that may be be the subject of clinical investigation, as well as the limitations, time limits, conditions and guarantees which, where appropriate, are established.

3. For the authorisation of subsequent clinical trials with an investigational medicinal product previously qualified as a product in the clinical investigation phase, the documentation referred to in Article 20.3 shall be updated where necessary. in accordance with the instructions for the conduct of clinical trials in Spain or, where appropriate, the guidelines of the European Commission, which shall be published by the Ministry of Health and Consumer Affairs.

Requests that are in accordance with the preceding paragraph shall refer to those circumstances.

Article 25. Modification of the conditions for the authorisation of clinical trials.

1. Any modification to the conditions authorised for a clinical trial which is considered relevant may not be carried out without the prior favourable opinion of the Ethics Committee for Clinical Research and the authorisation of the Agency. Spanish Medicines and Healthcare products.

Without prejudice to the foregoing, if the amendment refers exclusively to specific documents to be evaluated by the Ethical Committee of Clinical Research, only the favourable opinion of that committee will be required. for its application. On the other hand, if the modification concerns the documentation to be evaluated only by the Spanish Agency for Medicines and Health Products, only the authorization of the latter will be required.

If circumstances that could endanger the safety of the subjects were given, the sponsor and the investigator shall take appropriate urgent measures to protect the subjects from any immediate risk. The sponsor shall report as soon as possible to both the Spanish Agency for Medicinal Products and Health Products and to the Ethical Research Committees involved in the trial of those circumstances and the measures taken.

2. Relevant amendments are considered to be those detailed in the instructions for the conduct of clinical trials in Spain or, where appropriate, the guidelines of the European Commission, to be published by the Ministry of Health and Consumer Affairs.

3. The application must be submitted in writing, dated and signed by the promoter and researcher, to the Spanish Agency for Medicines and Health Products and to the appropriate Clinical Research Committees. The application shall be in accordance with the instructions for the conduct of clinical trials in Spain or, where appropriate, the guidelines of the European Commission, which shall be published by the Ministry of Health and Consumer Affairs.

4. The opinion shall be adopted in accordance with the procedure laid down in Articles 18 and 19. However:

(a) The Ethics Committee for Clinical Research concerned shall have a maximum period of 35 calendar days, from the notification of the admission to the processing of the application, to communicate its reasoned opinion to the sponsor, to the Coordinator of the Ethical Committees of Clinical Research, the Spanish Agency for Medicines and Health Products and, in the case of multicenter trials, the Ethical Committees of Clinical Research involved.

(b) In multicenter trials, the report of the Clinical Research Committees involved, other than the reference committee, will only be required when the change involves the incorporation of new centres or Lead researchers to the test, and will only be binding on the local aspects of the trial. Only the report of the ethics committee for the institution or researcher to be incorporated will be required.

5. The authorisation of the Spanish Agency for Medicinal Products and Sanitary Products shall be adopted in accordance with the procedure laid down in Articles 21, 22 and 23. However, the authorization shall be deemed to have been granted if within 35 calendar days of notification of the admission to the application of the application, the Spanish Agency for Medicinal Products and Sanitary Products does not communicate reasoned objections. to the applicant.

6. In case of modifications in clinical trials with medicinal products for gene therapy, somatic cell therapy (including xenogenic cell therapy), as well as all medicinal products containing genetically modified organisms, the For their authorisation, they may be extended, notifying the sponsor of the new deadline.

Article 26. 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 resolution of the Spanish Agency for Medicinal Products and Health Products in the following cases:

a) If the law is violated.

b) If the conditions of your authorization are altered.

(c) If the ethical principles set out in Article 60 of Law 25/1990 of 20 December of the Medication are not complied with.

d) To protect the subjects from the test.

e) In defense of public health.

2. The decision to suspend or revoke the approval of the test shall be taken after the appropriate procedure has been given, with the person concerned to decide within seven days of the notification of the commencement of the trial. of the procedure.

Once the decision referred to in the previous paragraph has been adopted, the Spanish Agency for Medicinal Products and Health Products shall notify the decision taken, with express indication of the reasons, to the Research Committees. Clinical participants, the European Commission, the European Agency for the Evaluation of Medicinal Products, the health authorities of the autonomous communities and the health authorities of the other Member States.

3. The health authorities of the autonomous communities may, on their own initiative or on a proposal from the relevant Ethics Committee for Clinical Research, resolve the precautionary suspension of the clinical trial in the cases provided for in paragraph 1; and shall immediately notify the Spanish Agency for Medicinal Products and Sanitary Products, which, in accordance with paragraph 2, shall resolve the suspension or revocation of the approval of the test or, where appropriate, the lifting of the measure. precautionary.

Article 27. Final report of the clinical trial.

1. Upon completion of the clinical trial, within 90 days, the sponsor shall notify the Spanish Agency for Medicinal Products and Sanitary Products and the ethical committees involved at the end of the trial.

2. In the case of early termination, within 15 days the sponsor shall forward to the Spanish Agency for Medicinal Products and Sanitary Products and to the Ethical Research Committees involved a report including the data obtained up to the the time of its early conclusion, as well as the reasons for it, and where appropriate the measures taken in relation to the subjects involved in the trial.

3. Within one year of the end of the test, the sponsor shall forward to the Spanish Agency for Medicinal Products and Health Products and to the Clinical Research Committees involved a summary of the final report on the results of the trial.

4. Where the duration of the test is longer than one year, it shall also be necessary for the sponsor to submit an annual report on the progress of the test.

5. In all cases, the instructions for conducting clinical trials in Spain or, where appropriate, the guidelines of the European Commission, which will be published by the Ministry of Health and Consumer Affairs, will be followed.

CHAPTER V

Compassionate use

Article 28. Compassionate use of medications.

1. The use of medicinal products in isolated patients and in the margins of a clinical trial of investigational medicinal products, including medicinal products for indications or conditions of use other than those for use, is understood by compassionate use of medicinal products. authorised, where the doctor under his sole responsibility considers it essential to use it.

2. In order to use a medicinal product under the conditions of compassionate use, the informed consent of the patient or his legal representative shall be required, a clinical report in which the physician justifies the need for such treatment, the conformity of the director of the centre where the treatment and authorisation of the Spanish Agency for Medicines and Health Products is to be applied.

3. The responsible doctor will communicate the results of the treatment to the Spanish Agency for Medicines and Health Products, as well as the suspected adverse reactions that may be due to it.

Article 29. Continuation of treatment after completion of the test.

After the end of the trial, any continuation in the administration of the investigational medicinal product, as long as the medicinal product is not authorised for these conditions of use, shall be governed by the rules established for the compassionate use in the previous article.

CHAPTER VI

Economic aspects

Article 30. 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. This documentation shall be made available to the relevant Clinical Research Ethics Committee.

2. The competent health authorities for each health service shall establish the common requirements and financing conditions and the model of the contract in accordance with the general principles of coordination agreed by the Council. Interterritorial of the National Health System.

3. The contract shall include 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 it would not have been involved in the trial, such as additional analyses and additional scans, changes in the duration of care for patients, reimbursement for patients ' expenses, purchase of equipment and compensation for test subjects and researchers. They shall also consist of the terms and time limits for payments, as well as any other subsidiary liability that the parties contract.

CHAPTER VII

investigational drugs

Article 31. Manufacturing.

1. The manufacture of medicinal products not authorised in Spain for use in the field of a clinical trial may be carried out only after authorisation from the Spanish Agency for Medicinal Products and Sanitary Products. This authorisation shall be valid for the duration of the clinical trial in which they are used.

2. The manufacturer of an investigational medicinal product must be authorized for the exercise of his activity in accordance with the provisions of Royal Decree 1564/1992 of 18 December 1992 establishing and regulating the system of authorisation of the pharmaceutical laboratories and importers of medicinal products and the quality assurance of their industrial manufacture.

3. Where any of the stages of manufacture, such as final packaging, are carried out in a hospital pharmacy service, that service shall be excluded from the authorisation referred to in paragraph 2.

4. In all stages of the manufacture of an investigational medicinal product, the rules for the correct manufacture of medicinal products in the European Union, including Annex 13, published by the Ministry of Health and Consumer Affairs, should be followed.

Article 32. Import.

1. The importation of investigational medicinal products, for use in the field of a clinical trial, may be carried out only after authorisation from the Spanish Agency for Medicinal Products and Sanitary Products.

2. The importing pharmaceutical laboratory shall ensure that the medicinal product has been produced by a manufacturer duly authorised in the country of origin and which complies with the correct manufacturing standards, at least equivalent to those laid down by the Union. European, without prejudice to the liability of the sponsor established in Article 35.

3. The application for the manufacture or 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 manufacture or import of blood products, narcotic drugs or psychotropic substances shall be governed by their specific legislation.

Article 33. Tagged.

The labelling of investigational medicinal products must appear at least in the official Spanish language of the State and be in line with the requirements of Annex 13 to the rules for the correct manufacture of medicinal products in the Union. European.

CHAPTER VIII

Clinical Good Practice Standards

Article 34. Standards of good clinical practice.

All clinical trials with medicinal products to be performed in Spain must be carried out in accordance with the standards of good clinical practice published by the Ministry of Health and Consumer Affairs, provided that they do not object to the willing in this royal decree.

Article 35. 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 authorization to the Ethical Committee for Clinical Research 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.

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 Ethical Committee of Clinical Research and the authorization of the Spanish Agency for Medicines and Health Products, as well as to provide them with the information and to obtain the authorizations that come, without injury to the communication to the autonomous communities, in the event of modification or violation of the protocol or interruption of the test, and the reasons for this.

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.

Exceptionally, other supply paths may be agreed with the center.

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

(h) Communicate to the health authorities, the researchers and the Ethical Research Committees involved in the study the suspicions of serious and unexpected adverse reactions in accordance with the provisions of the Articles 43 to 46.

i) Provide the investigator and the Clinical Research Ethics Committee immediately with any relevant information that they have access to during the trial.

j) Provide economic compensation to the subjects in case of injury or death related to the trial. 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.

k) 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 or partial test reports and communicating them to the appropriate person.

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

Article 36. Monitor.

They are monitor responsibilities:

a) Work in accordance with the promoter's standard working procedures, visit the investigator before, during and after the test to check compliance with the protocol, ensure that the data are recorded correct and complete form, as well as ensure 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 properly informed and at all times ensure rapid communication between investigator and promoter.

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.

Article 37. Investigator.

1. The investigator directs and takes responsibility for the practical implementation of the clinical trial in a center, and signs together with the promoter the application, corresponding to him.

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) Agree and sign along with the promoter the protocol of the trial.

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) Immediately report serious or unexpected adverse events to the promoter.

f) 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.

g) Report regularly to the Clinical Research Ethics Committee of the trial march.

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

Article 38. Publications.

1. The promoter is obliged to publish the results, both positive and negative, of the clinical trials authorized in scientific journals and with mention to the Ethical Committee of Clinical Research that approved the study.

2. Where studies and research work on medicinal products are made public, the funds obtained by the author by or for the purpose of the research 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. The results or conclusions of clinical trials shall preferably be communicated in scientific publications before being disclosed to the non-healthcare public.

They will not be released prematurely or sensationalist treatments of efficacy not yet determined, nor will it be exaggerated.

5. The advertising of medicinal products in research is strictly prohibited, as laid down in Law 25/1990 of 20 December of the Medicamento, Royal Decree 1416/1994 of 25 June 1994 regulating the advertising of medicinal products medicines, Royal Decree 1907/1996 of 2 August 1996 on advertising and commercial promotion of products, activities or services with intended health purpose, and Law 34/1988 of 11 November, General Advertising.

Article 39. Clinical trial documentation file.

Documents constituting the master file of a clinical trial shall be kept for the duration and in accordance with the specifications set out in the Instructions for the conduct of clinical trials in Spain or, in its case, the guidelines of the European Commission to be published by the Ministry of Health and Consumer Affairs.

CHAPTER IX

Verifying compliance with good clinical practice standards

Article 40. Inspections.

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 Spanish Agency for Medicinal Products and Sanitary Products shall inform the European Agency for the Evaluation of Medicinal Products of the inspections carried out and their results.

It shall also be responsible for the introduction of the data relating to inspections in the European clinical trial database EUDRACT, as specified in the instructions for the conduct of clinical trials in Spain or, where appropriate, the guidelines of the European Commission, which will be published by the Ministry of Health and Consumer Affairs.

3. 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. test, the place of manufacture of the investigational medicinal product, any laboratory of analysis used in the clinical trial and/or at the premises of the sponsor.

4. After the inspection a report shall be drawn up which shall be made available to the inspected. It may also be made available to the Ethics Committee for Clinical Research involved, to the competent authorities in Spain and to the other Member States of the European Union and to the European Agency for the Evaluation of Medicinal Products, 5. It is for the Spanish Agency for Medicinal Products and Sanitary Products to seek the collaboration of the competent authorities of other Member States of the European Union and third States for the inspection of the test centre, promoter or facilities of the manufacturer of the investigational medicinal product established outside the national territory.

CHAPTER X

Communications

Article 41. Databases.

1. The Spanish Agency for Medicinal Products and Sanitary Products shall be responsible for the inclusion in the European database of EUDRACT clinical trials of data relating to clinical trials carried out on the national territory of the European Union. an agreement with the provisions set out in the instructions for the conduct of clinical trials in Spain or, where appropriate, the guidelines of the European Commission, which shall be published by the Ministry of Health and Consumer Affairs.

2. The Spanish Agency for Medicinal Products and Sanitary Products shall be responsible for keeping up to date its database of the authorised clinical trials carried out on the national territory.

The competent authorities of the Autonomous Communities shall have access to the data relating to the tests carried out in their territorial scope.

3. The Spanish Agency for Medicines and Health Products will make available to the public through its website information on the title of the trial, promoter, centres involved, pathology and population in clinical trials authorized.

There shall be no opposition, on the part of the sponsor of the test, to the publication of the above data from the trials promoted by him, provided that no indication is given against him in the application for authorisation of the clinical trial to the Spanish Agency for Medicines and Health Products.

CHAPTER XI

From surveillance to the safety of investigational drugs

Article 42. Obligations of investigators in the recording and reporting of adverse events.

1. The investigator shall immediately communicate to the promoter all serious adverse events, salt in the case of those referred to in the protocol or in the investigator's manual as events that do not require immediate communication. The initial communication shall be followed by detailed written communications. The test subjects shall be identified in the initial and follow-up communications by a specific code number for each of them.

2. Adverse events and/or anomalous laboratory results qualified in the protocol as determinants for safety assessments shall be communicated to the sponsor in accordance with the communication requirements and within the periods specified in the protocol.

3. In the event of a death of a subject participant in a clinical trial, the investigator shall provide the sponsor and the Ethical Research Committees concerned with all the additional information which may be given to him. request.

Article 43. Obligations of the sponsor in the registration, assessment and reporting of adverse events.

1. The sponsor shall keep detailed records of all adverse events reported to him by the investigators. These records shall be submitted to the Spanish Agency for Medicinal Products and Health Products when requested.

2. The promoter has an obligation to continuously assess the safety of investigational medicinal products using all the information at their disposal.

You must also communicate without delay to the Spanish Agency for Medicines and Health Products, to the competent bodies of the Autonomous Communities where the clinical trial is conducted and to the Ethical Research Committees. Clinical involvement of any important information affecting the safety of the investigational medicinal product. This communication shall be carried out in accordance with the criteria specified in the following Articles and in accordance with the procedures laid down in the instructions for the conduct of clinical trials in Spain or, where appropriate, guidelines for the European Commission, to be published by the Ministry of Health and Consumer Affairs.

3. The communication of safety information from the sponsor to the investigators shall follow the rules of good clinical practice.

Article 44. Expeditious notification of individual cases of suspected 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 suspicions of serious and at the same time unexpected adverse reactions associated with investigational medicinal products, whether they occur in Spain or in other States, and whether they have occurred in the approved clinical trial or in other clinical trials or in a different context of use, provided that such medicinal products are not marketed in Spain. For products placed on the market, including the medicinal product used as control or medicinal products used as concomitant medicinal products, the Spanish Agency for Medicinal Products and Health Products shall issue specific guidelines to be taken into account. the pharmacovigilance requirements in order to avoid potential duplication in the notification.

2. The maximum period of notification shall be 15 calendar days from the moment the sponsor has become aware of the suspected adverse reaction.

When suspected serious and unexpected adverse reaction has resulted in the death of the subject, or life threatening, the sponsor shall inform the Spanish Agency of Medicines and Health Products within the maximum period of seven years. natural days from the moment the promoter becomes aware of the case. Such information shall be completed, as far as possible, within eight days.

3. When suspected serious and unexpected adverse reactions occur in a double-blind clinical trial, the treatment code for that particular patient should be disclosed for notification purposes. Whenever possible, the blind character for the researcher will be maintained, and for the persons responsible for the analysis and interpretation of the results, as well as for the elaboration of the conclusions of the study. In cases where it is considered that this notification system may interfere with the validity of the study, a specific notification system may be agreed with the Spanish Agency for Medicines and Health Products.

4. Suspected adverse reactions attributable to placebo will not be subject to this individualized reporting system.

5. Notifications will be made preferably using the European standard electronic format.

When this is not possible, due to a justified reason, the paper notification form will be used for notifications of suspected adverse reaction events occurring in Spain. For notifications of suspected adverse reactions occurring outside Spain, an international standard form may be used. Notifications that occur in Spain, regardless of the format used, will have to be communicated in the official Spanish language of the State.

6. The Spanish Agency for Medicinal Products and Sanitary Products will maintain a data processing network to record all suspicions of unexpected serious adverse reactions of an investigational medicinal product of which it is aware. In addition to the reception of electronic communications, such a network will allow for the real-time access of autonomous communities and electronic communication to the European Agency for the Evaluation of Medicinal Products for suspected adverse reactions. unexpected serious events that have occurred in Spain.

Article 45. Expeditious notification of individual cases of suspected adverse reaction to the competent bodies of the Autonomous Communities.

1. The sponsor shall notify the competent bodies of the autonomous communities in whose territory the test is being conducted individually and within the maximum period of 15 days, all suspected adverse reactions which are at the same time serious and unexpected associated with the investigational medicinal product and which have occurred in selected patients in their respective territorial areas. This maximum period shall be seven days in the case of suspected adverse reactions resulting in death or life threatening. For medicinal products placed on the market, including those used as controls or those used as concomitant medicines, the Spanish Agency for Medicinal Products and Health Products shall issue specific guidelines which shall take into account the requirements of pharmacovigilance in order to avoid potential duplication in the notification.

2. The sponsor shall report any other information on serious and unexpected adverse reactions associated with the investigational medicinal product where the specific regulations of the Autonomous Communities so provide and, in any case, if the information is an important change in the security profile of the product under investigation.

3. When the sponsor makes the communication in electronic form, the notification to the Autonomous Communities shall not be required, since such information shall be accessible to them in real time through the data processing network.

Article 46. Expeditious notification of individual cases of suspected adverse reaction to the Ethical Committees of Clinical Research.

1. The sponsor shall notify the relevant ethical committees, individually and within a maximum period of 15 days, of all suspected adverse reactions which are both serious and unexpected associated with the investigational medicinal product and which have occurred. in selected patients in their respective areas. The maximum period shall be seven days in the case of suspected adverse reactions resulting in death or life threatening.

2. The sponsor shall notify any other information on serious and unexpected adverse reactions associated with the investigational medicinal product where the ethical committees concerned so provide at the time of the favourable opinion of the study and, any case, if the information represents a major change in the safety profile of the product under investigation. The ethical committees involved may provide that this additional information will be provided to you on a regular basis. The Spanish Agency for Medicines and Health Products, in line with the European provisions, will publish the relevant guidelines to guide promoters.

Article 47. Periodic safety reports.

1. In addition to the expeditious notification, clinical trial promoters shall prepare a periodic report assessing the safety of the investigational medicinal product taking into account all available information.

2. The periodic safety report shall be submitted to the Spanish Agency for Medicinal Products and Health Products, to the competent bodies of the corresponding Autonomous Communities and to the Clinical Research Committees involved, annually until the end of the test and whenever requested by the health authorities or the ethical committees involved.

3. The Spanish Agency for Medicinal Products and Health Products will determine the format of the periodic safety report, taking into account the European regulations in this respect. The periodic safety report shall not replace the application for amendments to the test documents, which shall follow its specific procedure.

4. Without prejudice to the frequency indicated for safety reports, the sponsor shall prepare an ad hoc assessment report whenever there is a relevant safety concern. This report shall be submitted without delay to the Spanish Agency for Medicinal Products and Health Products, to the competent bodies of the Autonomous Communities and to the Clinical Research Committees concerned.

5. The periodic safety report may be a part of the relevant annual and final report or be prepared independently.

CHAPTER XII

Violations

Article 48. Administrative infringements in the field of clinical trials.

They shall constitute administrative infractions as provided for in Article 108 of Law 25/1990 of 20 December of the Medication and shall be sanctioned in accordance with Article 109 of the same law.

Single additional disposition. Clinical trials with medical devices.

Clinical trials with medical devices will be governed by the principles set out in this royal decree in terms of application.

First transient disposition. Transitional arrangements.

The proceedings initiated prior to the entry into force of this royal decree will be governed by the provisions of Royal Decree 561/1993 of 16 April 1993 laying down the requirements for the conduct of tests clinical medicines.

Second transient disposition. Application of this royal decree to the health services of the Armed Forces.

As long as the forecasts contained in the second provision of Law 25/1990, of 20 December, of the Medicamento, are not developed, in the application of this royal decree to the health services of the The Armed Forces shall observe the following rules:

a) Correspond to the Ministry of Health and Consumer accreditation of the Ethical Committees of Clinical Research.

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.

Single repeal provision. Regulatory repeal.

Royal Decree 561/1993 of 16 April 1993 laying down the requirements for the conduct of clinical trials with medicinal products is hereby repealed, without prejudice to the provisions of the first transitional provision, and any other provision of equal or lower rank that opposes the provisions of this royal decree.

Final disposition first. Enabling title.

This royal decree has the character of legislation on pharmaceutical products for the purposes set out in Article 149.1.16. of the Spanish Constitution, and is adopted in the development of Title III of Law 25/1990, of 20 of December, of the Medication.

Final disposition second. Faculty of development.

The Minister of Health and Consumer Affairs is empowered to make the necessary provisions for the development of this royal decree, in accordance with the advance of scientific and technical knowledge and in accordance with the guidelines of the Union. European.

The Minister of Health and Consumer Affairs is also empowered to adopt the standards of good clinical practice and the instructions for conducting clinical trials in Spain, in accordance with the guidelines adopted by the Commission. European.

Final disposition third. Entry into force.

This royal decree will enter into force on May 1, 2004.

Given in Madrid, 6 February 2004.

JOHN CARLOS R.

The Minister of Health and Consumer Affairs,

ANA MARIA PASTOR JULIAN