Law 29/2006 of 26 July on guarantees and the rational use of medicinal products and medical devices provides in Article 24 for guarantees of the availability of medicinal products in specific situations and special authorisations.

In paragraph 3 of this article, the prescription and application of unauthorised medicinal products to patients not included in a clinical trial is permitted in order to meet special needs for treatment of situations. clinical trials of patients; this access to investigational medicinal products is known as compassionate use. As provided for in Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and control of medicinal products for human and veterinary use and establishing the European Medicines Agency, would be applicable in clinical situations committed, understanding as such chronic or seriously debilitating diseases or those that endanger the life of the patient, and that may be treated satisfactorily with an authorised and marketed medicinal product. Due to the characteristics of these situations, the compassionate use is limited to the hospital environment.

Regulation (EC) No 726/2004 provides for a common approach in the Member States on criteria and conditions for the compassionate use of new medicinal products prior to their authorisation, and provides for a the procedure for consultation of the Committee for Medicinal Products for Human Use of the European Medicines Agency by establishing the possibility of drawing up protocols for use with the aim of ensuring equity in access to these medicinal products in the European Union. These protocols, called in this royal decree temporary authorizations of use, allow, in addition, to speed up the administrative procedures in these clinical situations committed, since the patients who meet the indicated requirements They could access the medicine without the need for an individual authorization from the Spanish Agency for Medicines and Health Products.

Article 24 (3) of Law 29/2006 of 26 July states that the Minister for Health and Consumer Affairs shall lay down the conditions for the prescription of authorised medicinal products when used under conditions of different to those authorised, which in any case will be of exceptional character.

This precept has its origin in the fact that there are some circumstances in which clinical data which support a given therapeutic use for an already authorised medicinal product are not included in the of the medicine. This can be especially relevant in therapeutic areas where the research activity is very intense and the pace of evolution of scientific knowledge can precede the necessary procedures to incorporate these changes in the Technique of the medicine. There are also conditions of use established in clinical practice, but not contemplated in the authorization of the medicinal product, often due to the absence of commercial interest for carrying out the necessary studies to obtain the authorization of the Spanish Agency for Medicines and Health Products.

These exceptional uses of medicinal products under conditions other than those authorised fall within the scope of clinical practice, and therefore, in the area of responsibility of the prescriber, not requiring a authorisation on a case-by-case basis. However, there are certain situations in which it is recommended that the Spanish Agency for Medicines and Health Products issue a recommendation based on the evidence available on efficacy and safety.

To date, the use under conditions other than those authorised in the hospital field, was subject to the regime established for the compassionate use of investigational medicinal products, therefore it is necessary to establish a differentiated procedure for these two situations.

Moreover, Article 24 (4) of Law 29/2006 of 26 July provides for the possibility of authorising the importation of medicinal products which are not authorised and intended for use in Spain, provided that they are legally authorised in other countries, where this is essential for the prevention, diagnosis or treatment of specific pathologies because there is no suitable alternative in Spain authorised for that particular indication or for situations

In all these cases of use of medicinal products under special conditions, it is necessary to apply scrupulously what is established by Law 41/2002, of November 14, basic regulation of the autonomy of the patient and of rights and obligations in the field of information and clinical documentation, which establishes the right of the patient or user to decide freely, after receiving the appropriate information, between the available clinical options and also establishes the conditions for obtaining the patient's consent after providing the relevant information.

In the framework of the Administrative Burdens and Regulation Improvement Plan, it is necessary to simplify administrative burdens for applicants and to take advantage of the benefits of information technologies. and the communication. Therefore, the Spanish Agency for Medicinal Products and Sanitary Products will allow the telematic presentation of the requests referred to in this provision and will prepare the instructions that will collect the simplified application models.

This royal decree has the character of pharmaceutical legislation for the purposes provided for in Article 149.1.16. of the Constitution and is adopted in the development of Article 24 (3) and (4), and final provision of Law 29/2006 of 26 July, which is why, together with the provisions on the supply of medicinal products which regulate Articles 26 and 40 of Royal Decree 1345/2007 of 11 October 2007 regulating the authorisation, registration and conditions for the availability of medicinal products for human use manufactured industrially, completes the regulatory development of Article 24 of Law 29/2006 of 26 July, without prejudice to the direct application of paragraph 5 thereof in cases of suspected or confirmed spread of pathogens or chemicals, toxins or radiation nuclear.

Finally, in the process of elaboration of this standard, the Autonomous Communities, the Interterritorial Council of the National Health System and the sectors affected have been consulted among others.

In its virtue, on the proposal of the Minister of Health and Social Policy, with the prior approval of the Minister of Public Administrations, in agreement with the Council of State and after deliberation of the Council of Ministers in its June 19, 2009 meeting.

CHAPTER I

General provisions

Article 1. Object and scope of application.

1. In application of the provisions of Article 24 (3) and (4) of Law 29/2006, 26 July, of guarantees and the rational use of medicinal products and medical devices, this royal decree establishes:

(a) The requirements for the compassionate use, under exceptional conditions, of medicinal products in clinical research in patients who are not part of a clinical trial.

(b) The conditions for the prescription of authorised medicinal products where they are used under conditions other than those authorised, which shall in any event be of an exceptional nature.

(c) Access to unauthorised medicinal products in Spain provided that they are lawfully marketed in other States.

2. It is excluded from the scope of this royal decree the use of a medicinal product when its objective is research. Such a practice should be considered as a clinical trial and follow the rules in this respect.

Article 2. Definitions.

For the purposes of this royal decree:

1. Compassionate use of investigational medicinal products: use of a medicinal product prior to authorisation in Spain in patients suffering from a chronic or seriously debilitating disease or considered to be life-threatening and who cannot be treated successfully with an authorised medicinal product. The medicinal product concerned must be subject to a marketing authorisation application or must be subject to clinical trials.

2. Use of medicinal products under conditions other than those authorised: the use of medicinal products under conditions other than those covered by the authorised information sheet.

3. Access to unauthorised medicines in Spain: use of authorised medicinal products in other countries but not authorised in Spain, where they do not comply with the definition of compassionate use of investigational medicinal products.

Article 3. Guarantees of transparency.

The Spanish Agency for Medicines and Health Products (hereinafter the Agency) will ensure access to its decisions and recommendations referred to in this royal decree to health centres, to the competent authorities of the autonomous communities, the holder of the marketing authorisation for the medicinal product or its representative, the applicant for the marketing authorisation or the promoter of the investigational medicinal product, while preserving compliance with the product of the provisions of the Organic Law 15/1999, of 13 December, of Data Protection Personal character, and in Law 41/2002 of November 14, basic regulation of the autonomy of the patient and of rights and obligations regarding information and clinical documentation.

Article 4. Liability coverage.

The coverage of liability for damages arising from the assumptions provided for in this royal decree shall be governed by the provisions of Article 46 of Law 44/2003 of 21 November of the organisation of the professions health.

Article 5. Imports.

When medicinal products for use in this royal decree are required to be imported, this must be stated in the applications provided for in Chapters II and IV.

Article 6. Telematics presentation of requests.

The applications referred to in this royal decree, except in exceptional and duly justified cases, shall be submitted by means or telematic means to the Agency in accordance with the provisions of Article 27.6 of Law 11/2007, 22 of June, electronic access of citizens to Public Services.

The applications must also preserve compliance with the provisions of Organic Law 15/1999 of 13 December and Law 41/2002 of 14 November.

CHAPTER II

Compassionate use of investigational drugs

Article 7. Access to compassionate use of investigational drugs.

1. In accordance with the requirements set out in this Chapter, the Agency may authorise the compassionate use of investigational medicinal products, where the assumptions contained in the definition given to this term in Article 2.1 are verified.

On a prior basis, the clinical trial promoter or the marketing authorisation applicant shall state its readiness to provide the investigational medicinal product for compassionate use, as well as any other relevant information about this.

2. Access to the use of investigational medicinal products may be carried out by one of the following procedures:

a) Individualized access authority.

b) Temporary usage authorizations.

Article 8. Procedure for individualized access authorization.

1. The hospital centre will request access to investigational medicinal products on an individual basis to the Agency, prior to the approval of the Centre's Directorate. The application shall be accompanied by the following documentation:

(a) The clinical report of the responsible physician in which the need for the medicinal product is justified for the patient. The report should attach the documentation supporting the need to administer the medicinal product to the patient (reason why it cannot be satisfactorily treated with the authorised therapeutic alternatives, data supporting the use of the medicinal product). drug for the patient and reasons why the patient cannot be included in a clinical trial). The intended duration of treatment shall be indicated.

(b) The compliance of the clinical trial promoter or the applicant for the marketing authorisation in the cases that so requires.

c) The number of containers required.

2. The informed consent of the patient or his/her representative, although it will be essential prior to the administration of the medicinal product, will not be part of the application for authorisation to the Agency.

3. In the event that the application does not meet the requirements laid down, 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, he shall be given the withdrawal of his application.

4. Where the Agency considers that individual access cannot be authorised, it shall inform the applicant so that, within 10 days, it can make the allegations and provide the documentation it deems appropriate.

Article 9. Temporary authorisation of use of investigational medicinal products on the margins of a clinical trial.

1. The Agency may issue a resolution for the temporary authorisation of the use of investigational medicinal products on the margins of a clinical trial, in cases of medicinal products which are at an advanced stage of clinical research aimed at supporting a marketing authorisation, or for which the marketing authorisation has been applied for, and provided that it is intended to be used for a significant group of patients.

2. The temporary authorisation of use shall include the requirements and conditions under which the investigational medicinal product may be used outside the framework of a clinical trial without requiring an individual access authorisation. for each patient, and shall be made available to the persons concerned.

3. The sponsor of the clinical trials or the applicant for the marketing authorisation shall collaborate with the Agency to establish the conditions of use, on the basis of the results of the clinical investigation in progress.

4. The management of the hospital where the treatment is administered shall ensure, after having been approved for the application of the temporary authorisation of use at its centre, that the patient for whom the use of the medicinal product is proposed complies with the the conditions laid down in the temporary authorisation for use, and shall ensure that written informed consent is obtained prior to the administration of the medicinal product as laid down in Law 41/2002 of 14 November. It shall also, for information purposes, communicate to the Agency each of the patients receiving the temporary authorisation for use.

Article 10. Actions of the Agency.

The Agency, in access to investigational drugs outside the framework of a clinical trial, will be responsible for:

a) Authorize or deny individualized access to investigational drugs.

(b) Develop and grant temporary authorisations for use, in order to be drawn up by its network of experts, and take account of the opinions of the European Medicines Agency.

c) Modify, suspend or revoke temporary authorisations of use when new scientific data so advise to ensure patient safety and proper use of the medicinal product.

(d) Notify the temporary authorisations of use to the European Medicines Agency as provided for in Article 83 of Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004.

e) Communicate the competent authorities of the Autonomous Communities and the sponsor of the clinical trial or applicant for the marketing authorisation, the temporary authorisations of use and the safety concerns which appear with the uses referred to in this chapter.

f) Encourage and facilitate the inclusion of patients for whom the use of a investigational medicinal product for compassionate use has been requested, in the clinical trials promoted in relation to it.

g) Authorize the import of the drug, if any.

h) Establish an information system that enables the access of the competent authorities of the autonomous communities to individual authorizations.

i) Communicate to the clinical trial promoter or the marketing authorisation applicant the suspicion of serious adverse reactions within 15 days of receipt.

Article 11. Obligations of the doctor responsible for the treatment and management of the hospital.

1. A doctor who applies for access to an investigational medicinal product for patients not included in a clinical trial shall be responsible for:

a) Develop the clinical report supporting the need for treatment, including dosage and duration. The report shall clearly justify the reason why the administration of authorised medicinal products for the treatment of such medical condition and the lack of therapeutic alternatives is not considered appropriate.

b) Inform the patient in understandable terms of the nature of the treatment, its importance, implications and risks, and obtain his written informed consent or, where appropriate, that of his/her representative, in accordance with the established in Law 41/2002 of 14 November.

c) Immediately report suspected serious adverse reactions to the Agency.

d) Meet the specific forms of follow-up data collection when it is established in the individual authorization or in the temporary authorization of use.

e) Provide the Agency with any information it requests regarding the results of the treatment.

2. The application for individualised access and the use of the medicinal product under the conditions laid down in the temporary authorisation for use must be given the approval of the management of the hospital. In the case of temporary authorisations for use, the centre shall verify that the patient complies with the conditions laid down in the procedure; in the case of individual applications, he must obtain the express agreement of the sponsor of the clinical trials or the applicant for the marketing authorisation where required.

The healthcare facility will ensure that in all cases the written informed consent of the patient or their representative prior to the administration of the medicinal product is prescribed.

Article 12. Obligations of the sponsor of the clinical trials or the applicant for the marketing authorisation.

The promoter of the clinical trials or the applicant for the marketing authorisation of the investigational medicinal product, in the access to investigational medicinal products by patients not included in a clinical trial, shall be responsible for:

a) Collaborate with the Agency to define the conditions of the temporary authorization of use, based on the available results of efficacy and safety.

(b) Notify the Agency immediately of any data relating to the safety of the medicinal product which may have an impact on the effects of the authorisations for compassionate use.

(c) Communicate to the Agency the cases in which their express agreement is required prior to the supply of the medicinal product.

d) Confirm to the Agency the availability of the medicinal product for patients who fulfil the conditions of the temporary authorisation of use up to the time of the placing on the market of the medicinal product or the end of the authorisation temporary usage, and ensure provisioning.

CHAPTER III

Access to medicines under conditions other than authorized

Article 13. Requirements for access to medicinal products under conditions other than those authorised in Spain.

1. The use of medicinal products authorised under conditions other than those laid down in its technical fiche shall be of an exceptional nature and shall be limited to situations in which therapeutic alternatives authorised for a given purpose are not available. patient, respecting in his case the restrictions that have been established related to the prescription and/or dispensing of the medication and the therapeutic protocol of the health center. The physician responsible for the treatment should adequately justify in the medical history the need for the use of the medicinal product and inform the patient of the potential benefits and potential risks, obtaining their consent according to the Law 41/2002 of 14 November.

2. The Agency may draw up recommendations for use where a risk to patients arising from the use of a medicinal product under conditions not covered by the technical information sheet, in the case of medicinal products, could be reasonably foreseen. subject to restricted medical prescription, in accordance with Royal Decree 1345/2007 of 11 October 2007, or where the use of the medicinal product under these conditions would have a relevant impact.

The use of authorised medicinal products under conditions other than those laid down in its technical fiche, following the recommendations of use issued by the Agency, shall in any event be met with the requirements laid down in the Previous section.

3. The recommendations to be issued by the Agency shall be taken into account in the development of healthcare therapeutic protocols for healthcare facilities.

Article 14. Actions of the Agency.

The Agency, in access to medicines under conditions other than those authorised, shall be responsible for:

a) Develop recommendations for use in the assumptions specified in Article 13. These recommendations shall be based on the efficacy and safety data available, also reviewing the results of the clinical trials of which it has knowledge and the risk management plan for the medicinal product. The Agency may, for its preparation, have its network of experts and collect information from the marketing authorisation holder.

b) Establish an information exchange system with the competent authorities of the Autonomous Communities.

c) Review the recommendations when the new data so advises.

d) Inform the marketing authorization holder about the recommendations for use.

e) Notify of suspected adverse reactions to the marketing authorisation holder, as provided for in Royal Decree 1344/2007 of 11 October 2007 on the regulation of pharmacovigilance for medicinal products human use.

Article 15. Obligations of the physician responsible for treatment.

The doctor responsible for the treatment will be obliged to:

(a) Inform the patient in understandable terms, of the nature of the treatment, its importance, implications and risks, and obtain their consent under Law 41/2002 of 14 November.

b) Notify of suspected adverse reactions as provided for in Royal Decree 1344/2007 of 11 October 2007.

c) To respect in your case the restrictions that have been established linked to the prescription and/or dispensation and the therapeutic health care protocol of the health center.

Article 16. Obligations of the marketing authorisation holder of the medicinal product.

The marketing authorisation holder of the medicinal product shall be obliged to:

a) Notify of suspected adverse reactions of which you are aware in accordance with Royal Decree 1344/2007 of 11 October 2007.

b) Not to promote the use of the medicinal product under conditions other than those authorised, nor to distribute any type of material which, indirectly, could stimulate its use.

c) Provide the Agency with any information regarding the medicinal product that may have an impact for the purposes of the recommendations for use.

CHAPTER IV

Medicines not authorised in Spain

Article 17. Requirements to apply for authorisation of the use of medicinal products not authorised in Spain but in other countries.

The Agency may exceptionally authorise access to medicinal products not authorised in Spain and intended for use in Spain where the following conditions are met:

(a) That the authorised medicinal product in Spain is not found with the same composition or in a pharmaceutical form that does not allow the treatment of the patient.

b) That there is no authorised medicinal product in Spain which constitutes an appropriate alternative for that patient.

You may also authorize access to medicinal products that are authorized in Spain not placed on the market, following the procedures set out in this chapter.

Article 18. Procedure for individualized access to unauthorized medicines in Spain.

1. The application for individualised access to a medicinal product not authorised in Spain shall be submitted to the Agency through the health authorities or centres designated by them or the management of the hospital and shall be accompanied by the next documentation:

a) Optional prescription of the medicinal product accompanied by a clinical report that will motivate the need for treatment for the patient and specify the estimated duration of treatment.

b) The number of containers required.

(c) Scientific documentation supporting the use of the medicinal product for the therapeutic indication requested, in exceptional cases where it differs from the collection on the technical fiche of the country of origin, together with the conformity of the titular laboratory if required.

Where it is necessary to obtain an unauthorised medicinal product in Spain due to the supply of the alternative authorised in Spain, the Agency may authorise the importation of the medicinal product without the need for the application is accompanied by the documentation referred to in this paragraph.

2. The informed consent of the patient or his/her representative, although it will be essential prior to the administration of the medicinal product, will not be part of the application for authorisation to the Agency.

3. In the event that the application does not meet the requirements laid down, 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, he shall be given the withdrawal of his application.

4. Where the Agency considers that individual access cannot be authorised, it shall inform the applicant so that, within 10 days, it can make the allegations and provide the documentation it deems appropriate.

Article 19. Procedure for access to medicinal products not authorised in Spain through a use protocol.

1. The Agency may develop protocols establishing the conditions for the use of an unauthorised medicinal product in Spain where its need is foreseen for a significant subpopulation of patients. Such use protocols may be made on a proposal from the competent authorities of the Autonomous Communities.

2. The health authorities or centres designated by them or the management of the hospital centre shall request the Agency for the quantity of the necessary medicinal product, indicating that the patient complies with the established protocol of use. In such cases, an individual authorisation by the Agency shall not be required.

Article 20. Actions of the Agency.

The Agency will be responsible for:

a) Authorize or deny individualized access to unauthorized medicines in Spain.

b) Develop the protocol of use for access to the unauthorised medicinal product in Spain, and modify it when the scientific data or the authorisations of new medicinal products so require, informing the holder of the marketing authorization (or the appropriate legal figure).

c) Authorize the import of the drug.

(d) make available to the competent authorities of the autonomous communities the protocols of use for their knowledge and dissemination to the health centres established in their territory, as well as information on the individual usage authorizations.

Article 21. Doctor's obligations.

1. The doctor responsible for the treatment will be obliged to:

(a) Prescribing and producing the clinical report supporting the need for treatment, including the reasons why the administration of authorised medicinal products is not considered appropriate for the patient, posology and the intended duration of treatment. In exceptional cases where the patient's conditions differ from those listed in the technical information sheet of the country of origin, scientific documentation supporting the use of the medicinal product for the requested conditions shall be provided.

b) Notify of suspected adverse reactions in accordance with the provisions of Royal Decree 1344/2007 of 11 October 2007 as regards the procedure for the notification of suspected adverse reactions.

c) Inform the patient in understandable terms about the nature of the treatment, its importance, implications and risks, and obtain its consent in accordance with the provisions of Law 41/2002 of 14 November.

d) Ensure, where appropriate, that the treated patients comply with the conditions of the authorized use protocol, and complete the follow-up data collection forms when required.

Article 22. Obligations of the marketing authorisation holder.

The marketing authorisation holder in the country of origin (or the appropriate legal figure) shall be obliged to:

a) Carry out the documentation required by the Agency.

(b) Notify of the suspected adverse reactions of which it became aware as set out in Royal Decree 1344/2007 of 11 October 2007 as regards the procedure for the notification of suspected reactions adverse events.

c) To confirm to the Agency the availability of the medicinal product for which individual or protocol access is requested, and to ensure supply.

d) Do not promote the use of the medication.

e) Ensure that the medicinal product is intended exclusively for the applicant centres.

Single additional disposition. Preparation of instructions for the application for medicinal products.

The Agency will draw up instructions on how to collect the models for access to the types of medicines provided for in this royal decree.

Single transient arrangement. Submission of applications by telematic means.

The submission of the applications provided for in this royal decree may be made within 1 year of the entry into force of the decree by any of the means provided for in Article 38.4 of Law No 30/1992 of 26 May 1992. November, the Legal Regime of Public Administrations and the Common Administrative Procedure. After that period the applications shall be submitted in the manner provided for in Article 6.

Final disposition first. Competence title.

This royal decree is issued under Article 149.1.16 of the Spanish Constitution, which attributes exclusive competence to the State in the field of legislation on pharmaceutical products.

Final disposition second. Regulatory development.

The head of the Ministry of Health and Social Policy is hereby authorized to make any provisions necessary for the implementation and development of this royal decree.

Final disposition third. Entry into force.

This royal decree will enter into force on the day following its publication in the "Official State Gazette".

Given at the Embassy of Spain in Singapore, on June 19, 2009.

JOHN CARLOS R.

The Minister of Health and Social Policy,

TRINIDAD JIMENEZ GARCIA-HERRERA