Advanced Search

Royal Decree 1246/2008, Of July 18, Approving The Authorization Procedure, Registration And Pharmacovigilance Of Veterinary Medicinal Products Manufactured Industrially Regulated.

Original Language Title: Real Decreto 1246/2008, de 18 de julio, por el que se regula el procedimiento de autorización, registro y farmacovigilancia de los medicamentos veterinarios fabricados industrialmente.

Subscribe to a Global-Regulation Premium Membership Today!

Key Benefits:

Subscribe Now for only USD$40 per month.

TEXT

The current rules on veterinary medicinal products have contributed to the fact that drugs are found in the market with proven guarantees of quality, safety and efficacy. However, in the light of the experience gained, the European Union has considered it necessary to adopt further measures to promote the functioning of the internal market, without forgetting at any time the achievement of the protection of human health, animal health, protection of the environment in the face of possible damage caused by the use of veterinary medicinal products, and the protection of animal welfare, for which progress is made in the incorporation of harmonised criteria and procedures for the evaluation and authorisation of medicinal products and is deepened in measures aimed at continuous assessment of the safety of the same.

In the field of veterinary medicinal products, it is particularly important that the waiting time is sufficient to eliminate the dangers posed by waste to health, as provided for in Regulation (EEC) No Council Regulation (EC) No 2377/1990 of 26 June 1990 laying down a Community procedure for the establishment of maximum residue levels of veterinary medicinal products in foodstuffs of animal origin.

Law 29/2006 of 26 July on guarantees and the rational use of medicinal products and medical devices sets out these criteria and procedures, the instrument being the instrument for which the most recent provisions are transposed. Community action on medicines. It should be borne in mind that veterinary medicinal products are a key element in the maintenance of animal husbandry in an appropriate state of health for the development of animal health, in the framework of Law 8/2003 of 24 April of animal health, for the purposes of it is imperative that the available veterinary medicinal products comply with the requirements and guarantees of quality, safety and efficacy.

The latest Community provisions are Directive 2004 /28/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001 /82/EC of the European Parliament and of the Council of 6 November 2001 on the establishing a Community code on veterinary medicinal products, which harmonises and collects in a single text the Community rules on veterinary medicinal products, and Commission Directive 2006 /130/EC of 11 December 2001 on the applies Directive 2001 /82/EC as regards the establishment of criteria for derogation from the a veterinary prescription requirement for certain veterinary medicinal products intended for food-producing animals.

The transposition of Directive 2001 /82/EC, as amended by Directive 2004 /28/EC as regards the scope of this royal decree, implies the repeal, inter alia, of a large part of Royal Decree 109/1995, of 27 January, on veterinary medicinal products. The amendment concerns a large number of precepts, making it necessary to draw up a new provision integrating the original rule and its amendments.

This royal decree transposes, almost entirely, the previously mentioned community directives.

The fundamental aspects of Directive 2001 /82/EC, as amended by Directive 2004 /28/EC, which are the subject of transposition in this royal decree, concern the need to improve the functioning of the authorisation procedures. for veterinary medicinal products, which is why the procedure for national authorisation, and in particular mutual recognition, has been revised in order to strengthen the possibility of cooperation between Member States. In addition to the same purpose, a new Community authorisation procedure called decentralised is created and guarantees of confidentiality are established in the assessment, transparency and publicity of the decisions.

The need to ensure adequate monitoring of the therapeutic effects and safety profile of each new medicinal product makes the marketing authorisation to be renewed five years after it has been granted. Once that authorisation has been ratified, the period of validity should normally be unlimited, without prejudice to the continued assessment of the risks through appropriate pharmacovigilance systems and studies on the use of medicinal products in the European Union. actual conditions of use.

Furthermore, the European legislative framework provides for the possibility of an authorised medicinal product not being marketed, stating that any authorisation which does not make the marketing of the medicinal product effective for three years Consecutive loss of validity. However, derogations from this rule should be established where they are justified on grounds of public health, animal health, general interest or other exceptional circumstances which are considered as such by the Spanish Medicines Agency. and Healthcare Products.

In order to apply the same criteria in the classification of the modifications of the marketing authorisation of the Community procedures to the modifications of the national marketing authorisations, adopts Commission Regulation (EC) No 1084/2003 of 3 June 2003 on the examination of amendments to the terms of the marketing authorisations for medicinal products for human use and veterinary medicinal products granted by the competent authority of a Member State.

Another essential aspect of the veterinary medicinal product is its identification and the information to be included in the labelling and the package leaflet of the veterinary medicinal product, as a guarantee of its correct use, promoting safety and efficacy in their use. Directive 2001 /82/EC, as amended by Directive 2004 /28/EC, on labelling and package leaflet aims to define common rules in the field, leaving a wide range of availability to national legislation, particularly in the field of related to guarantees of authenticity and correct identification, to ensure a high level of protection for users and to allow the correct use of medicinal products on the basis of complete and comprehensible information.

The matters covered by this royal decree transpose a large part of Directive 2001 /82/EC, as amended by Directive 2004 /28/EC, although Titles IV, VI and Title VIII and Title X have not been the subject of this Directive. transposition of the rules on the manufacture, import, possession, distribution and supply of veterinary medicinal products to be outside the scope of this rule.

In Law 29/2006 of July 26, the Spanish Pharmacovigilance System for Veterinary Medicinal Products is created. This royal decree lays down the obligations of each of the agents involved in this structure, the aim of which is to provide on a continuous basis the best possible information on the safety of veterinary medicinal products. It is thus possible to adopt appropriate measures in order to ensure that medicinal products available on the market have a favourable benefit-risk ratio for animals and users under the conditions of authorised use. The Technical Committee for Veterinary Pharmacovigilance is hereby established as a pharmacovigilance coordinating body. Finally, the European Commission has drawn up and published the guidelines contained in Volume 9A of the rules on medicinal products in the European Union which will apply to the exercise of pharmacovigilance for veterinary medicinal products, as well as its successive updates.

Annex I includes the structure and content of the registration file, that is, all administrative and technical requirements that must accompany the marketing authorization application.

In Annexes II and III, the content of the technical and package leaflet and the labelling, respectively, is laid down.

This royal decree is adopted under Law 29/2006, of July 26, and has the character of legislation of pharmaceutical products for the purposes provided for in article 149.1.16. of the Spanish Constitution, guaranteeing, in the concerning the processing of personal data, respect for the Organic Law 15/1999 of 13 December, the Protection of Personal Data, and its implementing regulations.

In the preparation of this provision, the sectors affected and the autonomous communities have been consulted.

In its virtue, on the proposal of the Ministers of Health and Consumer Affairs and the Environment, and the Rural and Marine Environment, with the prior approval of the Minister of Public Administrations, in agreement with the State Council deliberation of the Council of Ministers at its meeting on 18 July 2008,

D I S P O N G O:

CHAPTER I

General provisions

Article 1. Object.

This royal decree is intended to regulate veterinary medicinal products manufactured industrially or in the manufacture of which an industrial process is involved, and in particular:

a) The requirements of the request for marketing authorization.

(b) The procedures for the authorisation, suspension and revocation of the authorisation, as well as for amendments to the conditions of authorisation.

c) The Summary of Product Characteristics, Labelling and Package Leaflet.

d) The particular conditions for certain classes of medication.

e) The obligations of the holder.

f) Community procedures.

g) Pharmacovigilance.

(h) Registration in the register of medicinal products, including special medicinal products covered by Chapter IV.

Article 2. Definitions.

1. For the purposes of this royal decree:

(a) Veterinary or veterinary medicinal products: any substance or combination of substances which is present as a holder of curative or preventive properties in respect of animal diseases, or which may be administered to the animal in order to restore, correct or modify its physiological functions by exercising pharmacological, immunological or metabolic action or to establish a clinical veterinary diagnosis.

(b) Active substance: any matter, whatever its origin-human, animal, plant, chemical or otherwise-, to which an appropriate activity is attributed to constitute a medicinal product.

(c) Excient: that matter which, included in the galenic forms, is added to the active principles or to their associations for the purpose of serving them as a vehicle, enabling their preparation and stability, modifying their organoleptic properties or to determine the physico-chemical properties of the medicinal product and its bioavailability.

(d) Raw material: any substance-active or inactive-used in the manufacture of a medicinal product, whether unchanged, modified or removed during the course of the process.

e) Gallic form or pharmaceutical form: the arrangement to which the active substances and excipients are adapted to constitute a medicinal product. It is defined by the combination of the way in which the pharmaceutical product is presented by the manufacturer and the way in which it is administered.

(f) Premix for medicated feed: any veterinary medicinal product prepared in advance for the purpose of further manufacturing of medicated feed.

(g) medicated feed: any mixture of medicated premix and feed prepared prior to its placing on the market as such medicated feed and intended to be administered to animals without processing on the basis of curative, preventive or other properties of the medicinal product referred to in point (a).

(h) immunological veterinary medicinal product: a veterinary medicinal product administered to animals in order to induce active or passive immunity, or to diagnose the state of immunity.

i) Wait time: the period of time required between the last administration of the veterinary medicinal product to an animal, under normal conditions of employment and as provided in this royal decree, and the obtaining of products foodstuffs of that animal in order to protect public health by ensuring that such foodstuffs do not contain residues in quantities exceeding the maximum residue limits for active substances fixed in accordance with the Regulation (EEC) No 2377/1990 of the Council of 26 June 1990 laying down a Community procedure for the establishment of maximum residue limits for veterinary medicinal products in foodstuffs of animal origin.

(j) Common name: the Spanish Official Denomination (DOE) attributed to each active principle by the Spanish Agency for Medicinal Products and Sanitary Products, in its absence, the International Proprietary Name (INN) recommended by the World Health Organization or, failing that, the usual common name.

The Spanish Official Denomination must be equal, or as approximate as possible, saved to the linguistic needs, to the International Denomination established by the World Health Organization.

k) Dosification/concentration: the content of active substances expressed in quantity per unit of intake, volume or weight according to the presentation.

l) Primary conditioning: the package or any other form of conditioning that is in direct contact with the medicinal product.

m) Outer packaging: the packaging in which the primary packaging is placed.

n) Labelling: the information in the outer packaging or in the immediate packaging.

n) Summary of Product Characteristics or Summary of Product Characteristics: a document addressed to healthcare professionals, agreed between the competent authority and the marketing authorisation holder of the medicinal product, containing the necessary information on how to use the medicine safely and effectively, and the safety conditions for which the veterinary medicinal product has been authorised.

o) Package Leaflet: the written information addressed to the user, which accompanies the medication.

p) Presentation: each of the combinations in which the product is disposed for use including composition, pharmaceutical form, dose and format.

q) Format: number of units contained in the package and/or the contents of the package.

r) Adverse reactions: any reaction to a veterinary medicinal product that is harmful and involuntary, and which occurs in response to doses normally applied in animals for prophylaxis, diagnosis or treatment of diseases, or to restore, correct or modify physiological functions.

s) Adverse reaction in people: any reaction that is harmful and involuntary and takes place in a human being after exposure to a veterinary medicinal product.

t) Serious adverse reaction: any adverse reaction that causes death, may be life-threatening, causes a significant disability or disability or constitutes a birth defect or birth defect, or causes permanent or prolonged symptoms in treated animals.

u) Unexpected adverse reaction: any adverse reaction whose nature, severity or consequences are inconsistent with the summary of product characteristics.

v) Periodic Safety Report: the periodic report containing the records referred to in Article 66.g.

x) Post-marketing surveillance study: a pharmacepizootiological study or a clinical trial conducted in accordance with the terms of the authorization and conducted for the purpose of identifying or investigating a safety hazard for an authorised veterinary medicinal product.

and) Uncontemplated use: The use of a veterinary medicinal product that does not conform to the product information sheet, including incorrect use and serious abuse of the product.

z) homeopathic veterinary medicinal product: the product obtained from substances called homeopathic strains, in accordance with a homeopathic manufacturing process described in the European Pharmacopoeia, or in the Spanish Royal Pharmacopoeia; or in a pharmacopoeia used officially in a country of the European Union. A homeopathic veterinary medicinal product may contain several active substances.

2. In addition,

following definitions shall apply:

(a) Medicinal gases: gas or mixture of gases intended to come into direct contact with the animal body and which, acting mainly by pharmacological, immunological or metabolic means, is provided with properties to prevent, diagnose, treat, relieve, or cure diseases or ailments. Medicinal gases used in inhalation therapy, anesthesia, "in vivo" diagnosis, or for the preservation and transport of organs, tissues and cells for transplantation, provided that they are in contact with them.

Liquefied medicinal gases, liquid oxygen, liquid nitrogen and liquid nitrogen protoxide, as well as any other that with similar characteristics and use may be manufactured in the future.

(b) Holder of the marketing authorisation: is the natural or legal person responsible for placing the medicinal product on the market for which it has obtained the marketing authorisation. For this purpose, it shall be entered in the register of marketing authorisation holders.

(c) Representative of the marketing authorisation holder: the natural or legal person, normally known as the local representative, designated by the marketing authorisation holder to represent him in Spain.

d) Risks related to the use of the medicinal product:

1. Any risk related to the quality, safety and efficacy of the veterinary medicinal product with regard to human health and animal health.

2. ° Any risk of unwanted effects on the environment.

e) Benefit-risk ratio: an assessment of the positive therapeutic effects of the veterinary medicinal product in relation to the risks described above.

(f) Spanish Pharmacovigilance Pharmacovigilance System: the system for the identification, quantification, evaluation and prevention of the risks of the use of veterinary medicinal products, as well as the monitoring of the possible adverse effects of these on animals, people or the environment, as well as their presumed lack of efficacy and the detection of inadequate waiting times.

g) Abuse of a medicinal product: the intentional, persistent or sporadic use of a veterinary medicinal product which is accompanied by harmful physical or behavioural effects.

h) Good Veterinary Pharmacovigilance Practice: a set of rules or recommendations to ensure the authenticity and quality of the data collected in veterinary pharmacovigilance, which allow the assessment to be carried out in each the risks attributable to the veterinary medicinal product, the confidentiality of information relating to the identity of persons who have suffered or reported adverse reactions, and the identity of the persons involved in the suspected adverse reactions, and the use of uniform criteria in the assessment of notifications and in generating alert signals.

i) Line extension: the second and successive applications for authorisation and registration in the register of other pharmaceutical forms, routes of administration and doses of an already authorised medicinal product, as well as those changes which require the submission of a new application for authorisation, in accordance with the European standard governing the modification of the authorisation of medicinal products granted by the competent authority of a Member State. Likewise, the extension of a marketing authorisation to new target species.

j) Generic veterinary medicinal product: the medicinal product having the same qualitative and quantitative composition in active substances and the same pharmaceutical form, and whose bioequivalence with the reference medicinal product has been demonstrated by adequate bioavailability studies.

Article 3. Scope of application.

1. This royal decree applies to veterinary medicinal products, including medicated premixtures, manufactured industrially or in the manufacture of which an industrial process is involved.

2. This royal decree does not apply in respect of applications, assessment and authorisation for medicinal products listed in Annex I to Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 on the establishing Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing the European Medicines Agency. However, it shall apply in respect of the obligation of communication of placing on the market and the inclusion of trade in the Register of medicinal products.

3. They fall outside the scope of this royal decree:

(a) medicated feedingstuffs, which are regulated in Royal Decree 157/1995 of 3 February 1995 laying down the conditions for the preparation, placing on the market and use of medicated feedingstuffs, which may only be be prepared from medicated premixtures which have received a marketing authorisation in accordance with this royal decree;

(b) veterinary medicinal products based on radioactive isotopes;

(c) the additives covered by Regulation (EC) No 1831/2003 of the European Parliament and of the Council of 22 September 2003 on additives in animal nutrition;

(d) medicinal products for veterinary use for research and clinical development, which shall be governed by their specific rules;

(e) medicinal products prepared in pharmacy in accordance with a veterinary prescription for a particular animal or a small group of animals, known as masterways;

(f) medicinal products prepared in pharmacy in accordance with the indications of a pharmacopoeia and intended to be delivered directly to the final user, referred to as official preparations;

g) self-vaccines.

Article 4. Character of the marketing authorisation.

1. No veterinary medicinal product manufactured industrially or in the manufacture of which an industrial process is involved may be placed on the market without the prior marketing authorization granted by the Spanish Agency for Medicinal Products and Products. Health or the European Commission and registration in the Register of medicines, in accordance with the procedures laid down for each case.

Any modification, transmission, suspension or revocation of the authorization to place a veterinary medicinal product on the market must be authorised and entered in the Register of medicinal products which, for these purposes, will have the same the registration, constitutive character, except in the case of medicinal products authorised by the European Commission.

2. Where a veterinary medicinal product has obtained an initial marketing authorisation, any dosage/concentration, pharmaceutical form, route of administration and additional presentations, as well as any modifications and extensions which They must also obtain an authorisation. All such marketing authorisations shall be considered as belonging to the same overall marketing authorisation, in particular for the purposes of data protection, as well as for subsequent modifications of the authorisation which affect a whole set of medicinal products of the same holder containing the same active substance.

CHAPTER II

Medicines authorization

Section 1. Requests

Article 5. Requirements of the applicant for a marketing authorisation.

The applicant for the marketing authorisation for a veterinary medicinal product must be established in the European Union. The applicant may designate a legal representative with whom the actions resulting from the processing of the application for authorisation of the medicinal product or its subsequent amendments shall be understood. The applicant may also indicate in the application the marketing authorisation holder proposed for Spain.

Article 6. Application for marketing authorisation for industrially manufactured veterinary medicinal products.

1. Applications for authorization to place veterinary medicinal products on the market shall be submitted in any of the places provided for in Article 38.4 of Law No 30/1992 of 26 November 1992 on the legal system of public and public administrations. Common Administrative Procedure, addressed to the Spanish Agency for Medicines and Health Products.

In addition and as provided for in Article 38.9 of that law, applications may be submitted by telematic means.

2. The application model shall be adjusted to the one established by the Spanish Agency for Medicines and Health Products at any time, in accordance with the standard models approved by the European Commission.

3. The documentation shall be presented in Spanish at least. However, the Spanish Agency for Medicines and Health Products may establish that one or more parts of the scientific-technical documentation may be presented in another language.

4. Applications for authorisation for medicinal products shall be accompanied by the document supporting the payment of the fee corresponding to those provided for in Article 111 of Law 29/2006 of 26 July on guarantees and the rational use of medicinal products. and medical devices.

5. The application, the model of which can be obtained through the website of the Spanish Agency for Medicines and Health Products, must include at least the data and documents listed below. The dossier shall be submitted in a standardised format in accordance with Annex I:

(a) name or business name and address or registered office of the applicant and, where applicable, of the manufacturer or manufacturers, as well as the premises where it is manufactured;

b) name of the veterinary medicinal product;

c) qualitative and quantitative composition of all components of the veterinary medicinal product, including that of its international common name (INN) recommended by the World Health Organization (WHO), and its equivalent with the Spanish official name (DOE), where they have them, or the relevant chemical name in the absence of the above;

d) description of the manufacturing method;

e) therapeutic indications, contraindications and adverse reactions;

(f) dosage for the different animal species to which the veterinary medicinal product is intended, pharmaceutical form, method and route of administration and period of validity;

g) reasons for the precautionary and safety measures to be taken when the veterinary medicinal product is stored, when administering it to animals and when disposing of waste, together with an indication of the potential risks involved veterinary medicinal product may represent for the environment, for human health and animal health and for plants;

h) indication of the waiting time for medicinal products intended for food-producing animal species;

i) description of the control methods used by the manufacturer;

j) test results:

1. Pharmacists (physico-chemical, biological or microbiological).

2. Safety and residue study.

3. Preclinics and clinics.

4. º Tests to assess the risk the drug could pose to the environment. This impact will have to be studied and the particular provisions intended to limit it should be foreseen, on a case by case basis.

The documents and information relating to the results of the tests referred to above shall be accompanied by detailed summaries and reports of experts possessing the necessary technical and professional qualifications; and endorsed in the curriculum to accompany the report, which will form part of the relevant application and will be integrated into the authorisation file;

k) detailed description of the pharmacovigilance system and, where appropriate, the risk management system to be established by the applicant;

(l) a summary of the characteristics of the product in accordance with the structure provided for in Annex II, a model of the packaging, the packaging, if appropriate, and the labelling of the veterinary medicinal product and the package leaflet, with the structure and information provided for in Annex III;

m) a document stating that the manufacturer is authorised in his country to draw up the veterinary medicinal product;

n) where appropriate, a copy of the marketing authorisation obtained for the medicinal product in another Member State or in a third country, the technical information sheet and the package leaflet approved or proposed where appropriate, together with the list of Member States in which an application for authorisation is being considered. As well as any refusal of an application for authorisation, both in the European Union and in a third country, and the reasons for such a decision. Without prejudice to the provisions of Article 45.c), the updating of this information should be carried out provided that they reach the knowledge of the applicant or the holder of the authorisation, facts which affect or alter the information provided or worker in the request;

(n) a supporting document that the applicant has a qualified person responsible for pharmacovigilance, as well as the necessary infrastructure to report on any adverse reactions suspected or suspected of being produce in the European Union or in a third country;

o) prove that the pharmacologically active substance of the medicinal product intended for one or more food producing species has a maximum residue limit set out in Annex I, II or III to Regulation (EEC) No Council Regulation (EEC) No 2377/90 of 26 June 1990. In the case of not having a maximum residue limit established, a certificate certifying the presentation to the European Medicines Agency, six months earlier, of a valid application for the establishment of maximum residue limits, in the provisions of the said Regulation.

However, veterinary medicinal products containing pharmacologically active substances not included in the Annexes may be authorised provided that they are intended for specific animals of the family of equidae which are have been declared not intended for slaughter for human consumption in accordance with Commission Decision 93 /623/EEC of 20 October 1993 establishing the identification document (passport) to accompany equidae registered, and with Commission Decision 2000 /68/EC of 22 December 1999 on the amending Commission Decision 93 /623/EEC and regulating the identification of equidae for breeding and production. Such veterinary medicinal products shall not contain the active substances expressly prohibited in Annex IV to Council Regulation (EEC) No 2377/1990 of 26 June 1990 and shall not be used for the treatment of diseases in respect of of which a veterinary medicinal product intended for animals of the family of equidae has been authorised.

6. In the case of veterinary medicinal products intended exclusively for use in aquarium fish, birds of particular houses, messenger pigeons, terrarium animals, small rodents, ferrets and rabbits, used only as pet animals, the Spanish Agency for Medicinal Products and Sanitary Products may, for placing on the market in the national territory, derogate from the provisions of this Article, provided that such medicinal products do not contain substances the use of which requires a veterinary control and has been taken measures to prevent unauthorised use of such medicinal products in other animals.

7. The applicant or marketing authorisation holder shall be responsible for the accuracy of the documents and data presented.

Article 7. Specific requirements for the authorisation of generic veterinary medicinal products.

1. For generic veterinary medicinal products as defined in Article 2.2.j, the different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be regarded as an active substance unless have significantly different properties in terms of safety and/or efficacy, in which case the applicant shall provide additional data to demonstrate the safety and/or efficacy of the diversity of salts, esters or derivatives present in a the same active principle. The different oral pharmaceutical forms of immediate release will be considered as the same pharmaceutical form. The applicant may be exempt from presenting the bioavailability studies if it can demonstrate that the generic medicinal product satisfies the relevant criteria as defined in the relevant detailed guidelines.

2. Without prejudice to the right relating to the protection of industrial and commercial property, the applicant shall have no obligation to provide the results of the safety and residue studies tests and the pre-clinical and clinical trials if can demonstrate that the medicinal product is generic of a reference medicine which has been or has been authorised for at least eight years by a Member State or in the European Union by a centralised procedure. For these purposes, reference medicinal product is defined as that authorised on the basis of a complete dossier.

3. Where the reference medicinal product is not authorised in Spain, the applicant shall indicate in the application the name of the Member State in which it has been authorised and the date of authorisation. The Spanish Agency for Medicinal Products and Health Products shall ask the competent authority of the other Member State for confirmation within one month that the reference medicinal product is or has been authorised, together with the complete the reference medicinal product and, if necessary, any other documentation which it considers relevant.

4. Generic medicinal products authorised under this royal decree shall not be placed on the market until 10 years after the date of the initial authorisation of the reference medicinal product.

This 10-year period shall be extended to 13 years for veterinary medicinal products intended for fish, bees or other species designated for that purpose by the Commission.

5. In the case of veterinary medicinal products intended for one or more species producing food for human consumption and containing a new active substance which would not have been authorised in the European Union on 30 April 2004, the the 10-year period provided for in the preceding paragraph shall be extended by one year for each extension of the marketing authorisation to another food producing animal, provided that it is authorised within five years of the granting of the the initial marketing authorisation.

However, this period may not exceed 13 years in total for a marketing authorization.

The extension of the 10-year period to 11, 12 or 13 years for a veterinary medicinal product intended for species producing food for human consumption shall be granted only if the marketing authorisation holder has been also the one that has requested the fixing of the maximum residue limits for the species subject to the authorization, which must be accredited in the application for the extension of the authorization to the new species of food-producing destination of human consumption.

6. By way of derogation from this Article, where the medicinal product does not comply with the definition of a generic medicinal product in paragraph 1, where bioequivalence cannot be demonstrated by means of bioavailability studies or where there are differences in the active substances, the therapeutic indications, the dosage, the pharmaceutical form or the route of administration in respect of those of the reference medicinal product, the results of the safety and study tests shall be provided residues and appropriate preclinical and/or clinical trials.

Article 8. Specific requirements for the authorisation of biological veterinary medicinal products similar to another reference.

1. Applications for authorisation shall include the results of appropriate pre-clinical and clinical trials where a biological medicinal product similar to a reference biological product does not meet the conditions of the definition of generic medicinal products, due to differences related to raw materials or differences in the process of manufacture of the biological medicinal product and the reference biological medicinal product.

2. The documentation shall comply with the criteria set out in Annex I and shall comply with the detailed guidelines for each subject. The results of other tests and trials of the dossier for the reference medicinal product shall not be provided.

Article 9. Specific requirements for the authorisation of veterinary medicinal products based on well-established active substances.

1. The applicant shall have no obligation to provide the results of the safety and residue studies tests, or the results of pre-clinical and clinical trials of its own, if it can demonstrate that the active substance of the veterinary medicinal product has been well established veterinary use for at least 10 years within the European Union and presents a recognised efficacy as well as an acceptable level of safety under the conditions set out in Annex I.

2. In this case, the results of the tests will be replaced by a literature-scientific documentation that provides adequate scientific evidence.

3. This Article shall not apply to products which fulfil the conditions laid down in Articles 7 and 8.

4. The assessment report published by the European Medicines Agency, following the assessment of an application for the establishment of maximum residue limits under Council Regulation (EEC) No 2377/1990 of 26 June 1990, may be used as literature-scientific documentation, in particular as regards safety testing.

5. If an applicant uses a literature-scientific documentation in order to obtain an authorisation for a species producing food for human consumption, and presents for the same veterinary medicinal product, in order to obtain a authorisation for another food producing species, new residue studies under Council Regulation (EEC) No 2377/1990 of 26 June 1990, as well as clinical trials supporting the efficacy of the medicinal product in the new species of destination, no third party may resort to such studies and trials within the framework of Article 7 for a period of three years following the granting of the authorisation for that new species of destination.

Article 10. Requests for new authorized active principles associations.

Applications for veterinary medicinal products containing the association of active substances present in the composition of authorised medicinal products, but which have not yet been combined for therapeutic purposes, must be the results of the safety and residue studies tests, if necessary, and of the pre-clinical or clinical trials relating to the new association, without the need to provide the documentation relating to each individual active substance.

Article 11. Requests for authorisation of medicinal products with the express consent of the holder of a prior authorisation or of a registration file.

1. Following the granting of a marketing authorisation, the holder of the marketing authorisation may consent to the use of the pharmaceutical, safety and residue studies, pre-clinical and clinical documentation on the dossier of his/her by another applicant. for the study of a subsequent application for a medicinal product having the same qualitative and quantitative composition in active substances and the same pharmaceutical form. This situation must be certified by both parties in the documentation accompanying the second application, meaning the accuracy of both dossiers in all pharmaceutical, safety and residue studies, preclinical and clinical aspects, except in the identification and labelling aspects of the medicinal product.

2. The applicant for a pending file may, in addition, consent to the submission of another application based on identical pharmaceutical, safety and residue studies, pre-clinical and clinical documentation, accompanying the second dossier certification by both of this authorization and the accuracy of both documentation in all pharmaceutical, safety and residue studies, preclinical and clinical aspects, except in the identification and labelling aspects of the medication.

Article 12. Exceptional requests for immunological veterinary medicinal products.

In the case of immunological veterinary medicinal products and in exceptional circumstances, the applicant shall not be obliged to make or to provide the results of certain field tests carried out in the species of destination, if there are grounds for failure to do so, and in particular where Community legislation so provides.

Section 2. Authorization Procedure

Article 13. Objectives of the authorisation procedure.

1. The purpose of the authorisation procedure is to verify that the veterinary medicinal product:

a) Reaches established quality requirements.

(b) It is safe, not producing under normal conditions of use toxic or undesirable effects on animals, consumers of products of animal origin and the environment, disproportionate to the benefit of the animal.

c) It is effective in approved therapeutic indications.

d) It is correctly identified and is accompanied by accurate information for use.

2. The assessment of the therapeutic effects of the medicinal product shall be assessed in relation to any risk related to the quality, safety and efficacy of the medicinal product for public health, animal health and the environment, understood as benefit/risk ratio.

3. The provisions of this Article shall also apply to changes in the authorisation and shall remain applicable, as long as the product is on the market, in accordance with the new evidence concerning its security and effectiveness will be obtained.

4. At any time the Spanish Agency for Medicines and Health Products may review the requirements of paragraph 1.

Article 14. Confidentiality guarantees.

The documentation for the authorization request and expert reports will be confidential.

Article 15. Admission to processing and validation of the application.

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

2. Where 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, his application shall be filed, after a decision has been taken. (a) the terms laid down in Article 42 of Law No 30/1992 of 26 November.

3. The maximum time limit for the notification of the decision of the authorisation procedure for the medicinal product shall be 210 calendar days, which shall begin to be computed from the day following the date of submission of a valid application.

4. Where the medicinal product covered by the application has previously been authorised in another Member State, no application may be made to the Spanish Agency for Medicinal Products and Sanitary Products and shall not be allowed to be processed unless the application has been made. is presented in accordance with the mutual recognition procedure.

5. Where the medicinal product covered by the application is being evaluated in another Member State, it shall be communicated by the applicant to the Spanish Agency for Medicinal Products and Sanitary Products. The Spanish Agency for Medicinal Products and Sanitary Products will not accept the application and inform the person concerned that they will have to process their application by mutual recognition procedure or by decentralised procedure.

Article 16. Assessment of the pharmaceutical, safety and residue, pre-clinical and clinical documentation and issue of the relevant report.

1. The Spanish Agency for Medicinal Products and Health Products shall carry out the evaluation of the dossier and issue an assessment report. To this end, it may require additional documentation or clarifications from the applicant on any extreme subject of the application, setting a period of three months, which may exceptionally be extended to six months, for the submission of such an application. documentation. Where the Spanish Agency for Medicinal Products and Sanitary Products makes use of this option, the time limits provided for in the previous Article shall be suspended until the required supplementary data are provided or the time limit is concluded.

2. The assessment report shall be reasoned and shall cover the pharmaceutical, safety and residue, pre-clinical and clinical aspects of the medicinal product.

3. In the evaluation process, the Spanish Agency for Medicinal Products and Sanitary Products may subject the medicinal product, its raw materials, intermediate products and other components to the examination of its official control laboratories. It may also request the collaboration of another national laboratory accredited to that effect by the Agency itself, an official Community control laboratory or a third country. In the case of immunological veterinary medicinal products, once authorised, and without prejudice to the provisions of Article 63 of Law 8/2003 of 24 April, of animal health, the Spanish Agency for Medicinal Products and Sanitary Products, may subject the medicinal product to the controls necessary for the official batch release, either documentary or analytical in the official control laboratories.

4. The Spanish Agency for Medicinal Products and Sanitary Products may verify through the national or Community reference laboratory that the analytical method for the detection of residues presented by the applicant is satisfactory.

Article 17. Opinion of the Committee for the Evaluation of Medicinal Products for Veterinary Use.

The Spanish Agency for Medicinal Products and Sanitary Products may ask the Committee for the Evaluation of Medicinal Products for Veterinary Use for its opinion on applications for new authorisations for medicinal products, and applications for Major modifications of marketing authorisations, for which the assessment report and, where appropriate, a proposal of the technical information sheet and the prospectus shall be submitted to that Committee.

In any event, the opinions of the Committee for the Evaluation of Medicinal Products for Veterinary Use shall not be binding, except for reasons of public health or animal health, where the reasoned report is required in this case, with Article 60 of Law 8/2003 of 24 April.

Article 18. Grounds for refusal and motion for a resolution.

1. The application for authorisation of a medicinal product may be refused on a reasoned basis if any of the following conditions are met:

(a) the benefit-risk ratio of the veterinary medicinal product is not favourable under the conditions of use applied for; where the application relates to veterinary medicinal products for zootechnical use, account shall be taken of the the health and welfare benefits of the animals, as well as the safety of the consumer;

(b) the veterinary medicinal product has no therapeutic effect or is insufficiently justified by the applicant for the animal species to be treated;

(c) the veterinary medicinal product does not have the declared qualitative or quantitative composition;

(d) that the waiting time indicated by the applicant is insufficient to ensure that the foodstuffs from the treated animal do not contain residues which may present a danger to the health of the consumer, or insufficiently justified;

(e) the veterinary medicinal product is to be sold for unauthorised use under other Community provisions. However, where such a decision is still to be taken within the Community regulatory framework, the Agency may refuse the authorisation of a veterinary medicinal product if such a measure is necessary to ensure the protection of the public health of consumers or animal health.

f) When the data and information contained in the documentation of the application for authorization are erroneous or do not comply with the rules of application in the matter.

2. Where the outcome of the assessment is unfavourable for any of the reasons set out in the preceding paragraph, or the content of the technical fiche may entail changes which are considered to be substantial in respect of the proposal made by the the applicant, the Subdirectorate-General for Medicinal Products for Veterinary Use of the Spanish Agency for Medicinal Products and Sanitary Products shall make it clear to the person concerned that, within a period of 15 days, he may make the allegations and present the documentation that you consider appropriate.

3. Claims made by the applicant, the Spanish Agency for Medicinal Products and Sanitary Products may amend the assessment report and, if appropriate, in accordance with the previous Article, be referred to the Evaluation Committee for Medicinal products for veterinary use, in order to issue the appropriate opinion.

Article 19. Resolution.

1. When the results of the evaluation are favourable, the Spanish Agency for Medicines and Health Products shall issue a resolution authorizing the placing on the market.

2. The approval of a medicinal product shall contain the conditions of authorisation and shall form part of the administrative data, the information sheet, the labelling and the package leaflet.

3. The authorisation document shall contain at least the following information:

a) Name of the medication.

b) Record number.

c) Therapeutic group.

d) Pharmaceutical form.

e) The path of administration.

f) Target species.

g) Wait times, if applicable.

h) Formats authorized with their respective National Codes.

i) Conservation conditions and validity period.

j) Prescription and dispensing conditions.

k) Name and address of the authorization holder.

l) Name and address of the representative of the marketing authorisation holder, where appropriate.

m) Name and address of the manufacturer, both of the active substance and of the medicinal product in case they differ.

n) Full qualitative and quantitative composition.

4. The decision to reject the application for the authorisation of a medicinal product shall be reasoned and shall be adopted on the basis of a report from the Committee for the Evaluation of Medicinal Products for Veterinary Use, and the resources to be expressed shall be expressed. against the same, in accordance with the provisions of the current legislation.

5. Marketing authorisations may be subject to certain obligations in respect of safety or health protection, including special precautions for use and other warnings resulting from the use of such products. clinical and pharmacological tests, or following the marketing, resulting from experience gained in the use of the veterinary medicinal product, which the holder shall reflect in accordance with the provisions of Annex III, Part II, paragraph 9.

Article 20. Registration in the Register of medicines.

1. The authorisation of the medicinal product shall be entered in the Register of Medicinal Products of the Spanish Agency for Medicinal Products and Sanitary Products.

2. Each registration number shall relate only to one composition, one pharmaceutical form, one dose per unit of administration including all formats for sale. Each of the formats will be identified by their corresponding National Code.

In the case of a medicinal product to be administered with an exclusive applicator device that allows it to be used repeatedly, a presentation with an applicator device and another without it, may be permitted in the same register. assigning a National Code to each of the presentations.

3. In the case of medicinal products listed in Annex I to Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004, the placing on the market shall be communicated to the Spanish Agency for Medicinal Products and Products Health care for the purposes of their inclusion of trade in the Register of medicinal products.

Article 21. Transparency and publicity.

1. The Spanish Agency for Medicinal Products and Sanitary Products shall ensure public access to its decisions on the authorization to place a medicinal product on the market, its modifications, suspensions and revocations, when all of them are firm en route administrative, as well as the technical information will be publicly accessible, in accordance with the provisions of the Organic Law 15/1999, of December 13, of Protection of Personal Data.

2. The reasoned assessment report shall also be publicly accessible, subject to the deletion of any commercial information of a confidential nature, in accordance with the guidelines to be adopted by the European Commission.

Article 22. Responsibility of the holder and the manufacturer.

1. The marketing authorisation holder for each medicinal product shall be responsible for the fulfilment of the obligations arising from the authorisation and shall have the material and personal means necessary to fulfil the obligations. derived from it.

2. The authorisation of a medicinal product shall be granted without prejudice to the civil or criminal liability of the manufacturer or manufacturers, and the manufacturer or manufacturers involved in the process of manufacture of the product or its raw material, and in its the case of the marketing authorisation holder.

Article 23. Conditions for the prescription and dispensing of veterinary medicinal products.

1. It is for the Spanish Agency for Medicinal Products and Sanitary Products to lay down the conditions for the prescription and supply of veterinary medicinal products in accordance with the scientific assessment of applications for authorization to marketing and the criteria set out in this article.

2. The conditions for dispensing shall be part of the conditions of authorisation of the medicinal product and shall be reflected in the packaging material of the medicinal product in accordance with the symbols, acronyms and legends set out in Annex III.

These conditions of dispensing of veterinary medicinal products may be classified into two groups, depending on the medications:

(a) subject to veterinary prescription, with the following subcategories:

1. Medicines administered exclusively by the veterinarian.

2. Medicines administered under the control or supervision of the veterinarian.

3. Medicines only subject to prescription.

(b) not subject to veterinary prescription, including those provided for in Article 6.6.

Article 24. Veterinary medicinal products subject to prescription.

Without prejudice to stricter Community or national rules concerning the supply of veterinary medicinal products and to protect human health and animal health, veterinary prescription for the supply of veterinary medicinal products shall be required. all veterinary medicinal products subject to such a requirement in their marketing authorisation and in any case, of the following veterinary medicinal products:

a) Medicines whose supply or use are subject to official restrictions, such as:

1. The restrictions resulting from the application of the relevant United Nations conventions against the illicit trafficking of narcotic and psychotropic substances.

2. º Restrictions arising from Community or national legislation.

(b) Veterinary medicinal products intended for food-producing animals. However, veterinary medicinal products which meet all of the following criteria may be exempted from this requirement:

1. The administration of the veterinary medicinal product is limited to formulations that do not exempt any knowledge or ability for use.

2. The veterinary medicinal product does not involve any direct or indirect risk, even if it is administered incorrectly, for treated animals, the people who administer it or the environment.

3. The Summary of Characteristics or Summary of Product Characteristics of the veterinary medicinal product does not contain any warning of any serious side effects resulting from the correct use of the medicinal product.

4. The veterinary medicinal product or other product containing the same active substance has previously been the subject of frequent notification of a serious adverse reaction.

5. The Summary of Characteristics or Summary of Product Characteristics of the medicinal product does not refer to contraindications related to other types of commonly used veterinary medicinal products.

6. The veterinary medicinal product must not be subject to particular storage conditions.

7. º There is no risk to the safety of consumers as regards residues in food obtained from treated animals, even in the case of incorrect use of veterinary medicinal products.

8. There is no risk to human or animal health as regards the development of resistance to antimicrobials or antihelmintics, even if the veterinary medicinal products are used incorrectly. contain these substances.

(c) Medicinal products for which veterinary surgeons are required to take special precautions in order to avoid unnecessary risks, including the use of an anaesthetic or anaesthetics, to:

1. The species to which they are intended.

2. º The person administering such medications to the animals.

3. The environment.

(d) Those intended for pathological treatments or processes requiring an accurate diagnosis prior to the administration of the medicinal product, or for which the use may result in consequences that hinder or interfere with the actions subsequent diagnostic or therapeutic.

e) Veterinary immunological drugs.

f) The medicinal gases.

The Spanish Agency for Medicinal Products and Sanitary Products will also establish, in the corresponding marketing authorisations, the requirement of prescription for all new veterinary medicinal products which contain an active substance for which the use in veterinary medicinal products is less than five years authorised.

Article 25. Authorisations subject to special conditions.

1. In exceptional circumstances, the Spanish Agency for Medicinal Products and Sanitary Products may grant a marketing authorisation subject to the requirement that the applicant submit specific procedures, in particular with regard to to the safety of the veterinary medicinal product, to the notification to the competent authorities of any incident related to its use and to the measures to be taken. Such authorisations may be granted only where there are objective and verifiable reasons for this.

2. In these circumstances, the authorisation granted by the Spanish Agency for Medicines and Health Products shall be subject to a conditional, annual review and subject to the obligation on the part of the applicant to comply with the conditions laid down.

Article 26. Period of validity and renewal of the authorisation.

1. The authorisation of a medicinal product shall be valid for five years. That period may be renewed after a reassessment of the benefit/risk ratio. Once the authorisation has been renewed, it shall be indefinite, unless the reasons for pharmacovigilance justify its submission to a new renewal procedure.

2. The renewal procedure shall be initiated at the request of the holder of the authorisation of the medicinal product. The application shall be submitted to the Spanish Agency for Medicinal Products and Sanitary Products, at least six months before the expiry of its validity, and shall contain a consolidated list of all the documents submitted in respect of quality, safety and efficacy, including all variations introduced since the granting of the marketing authorisation. The Spanish Agency for Medicines and Health Products may at any time request the applicant to submit the documents listed.

3. The application for renewal shall be submitted in any of the places provided for in Article 38.4 of Law 30/1992 of 26 November, in accordance with the format of application published by the Spanish Agency for Medicines and Health Products.

4. The Spanish Agency for Medicinal Products and Health Products shall notify the decision before the expiry of the validity of the authorisation. In case the resolution is negative, the provisions of Article 52 shall be followed.

5. The authorisation shall be extinguished if no application for renewal of the authorisation is submitted within the prescribed period, unless the Spanish Agency for Medicinal Products and Sanitary Products maintains the validity of the authorisation.

Article 27. Effective marketing.

1. The holder of the authorisation shall communicate to the Spanish Agency for Medicinal Products and Sanitary Products the effective date of placing on the market of each medicinal product. That communication shall be made for each of the authorisations granted to the medicinal product at least 15 days before the marketing is made.

2. The holder of the authorisation shall make an annual declaration of intention to place the medicinal product on the market. This communication shall be made to the Spanish Agency for Medicinal Products and Health Products for the month of October of the previous year, accompanied by a justification for the payment of the corresponding fee provided for in Article 111 of the Law. 29/2006, dated 26 July. In the event of failure to submit this declaration, it shall be understood that the suspension of the marketing authorisation is requested in accordance with Article 53, the corresponding procedure being initiated.

3. Each marketing authorisation for a medicinal product shall be valid if, within three years, the holder does not proceed to the effective marketing of the medicinal product. The three-year period shall begin to be counted from the day following the date of notification of the decision of approval issued by the Spanish Agency for Medicinal Products and Sanitary Products.

4. Authorisation to place a medicinal product on the market shall also lose its validity, if once authorised and marketed it is no longer effective on the market for three consecutive years.

5. Where health or health concerns or other exceptional circumstances are considered as such by the Spanish Agency for Medicinal Products and Sanitary Products, or may be originated in therapeutic vacuum, the Spanish Agency of Medicines and Sanitary Products will maintain the validity of the authorisation and will require the effective marketing of the medicinal product.

6. The Spanish Agency for Medicinal Products and Sanitary Products will record the previous circumstances in the Register of Medicines.

Article 28. Exceptional marketing authorisations for veterinary medicinal products.

The Spanish Agency for Medicinal Products and Sanitary Products may provisionally authorise the administration and use of veterinary medicinal products authorised in another Member State, under the responsibility of the holder of the authorisation, prior to the report issued by the Ministry of the Environment, and the Rural and Marine Environment, when required by the health situation and under the conditions to be determined.

Article 29. Authorisation for the use of immunological medicinal products in a serious epizootic situation.

1. In the case of serious epizootic diseases, and in the absence of an appropriate and authorised medicinal product in Spain, the Spanish Agency for Medicinal Products and Sanitary Products may provisionally authorise the use of medicinal products. Veterinary immunological veterinary medicinal products without marketing authorisation, prior to the mandatory reporting and requirement of the Ministry of the Environment, and the Rural and Marine Environment, after having informed the European Commission of the detailed conditions of usage.

2. The Spanish Agency for Medicinal Products and Sanitary Products may authorise, subject to the report of the Ministry of the Environment, and the Rural and Marine Environment, the importation and use of an immunological veterinary medicinal product which is not authorised for placing on the market in Spain, but authorised in a third country, for an animal that is imported or exported to or from a third country, and is therefore subject to mandatory specific health provisions.

In this case, the Ministry of the Environment, and the Rural and Marine Environment, may allow this medicinal product to be administered and shall take all appropriate measures it deems appropriate in relation to the control of the said medicinal product, collected in the authorization.

CHAPTER III

Labelling and Package Leaflet

Section 1. General Provisions of Labelling and Package Leaflet

Article 30. Objectives of the labelling and package leaflet: Identification guarantees and information for the rational use of the medicinal product.

1. The labelling and package leaflet of the medicinal product shall be in accordance with the information on the technical information sheet.

2. The labelling and the package leaflet shall ensure the unambiguous identification of the veterinary medicinal product, providing the necessary information for correct administration and use by users and, where appropriate, by healthcare professionals. This guarantee of identification and information must be observed if the authorised format of the veterinary medicinal product permits its dispensing in a fractionated manner, that is, that there is no handling of the packaging in any case. primary of the medicinal product.

For the correct use of the medicated premixtures, the conditions for the preparation of the medicated feed and the stability of the medicated premix in the feed should be included in the labelling and the package leaflet.

3. The labelling and package leaflet, in their design and content, shall facilitate the appropriate understanding and knowledge of the medicinal product. The package leaflet must be legible and clear, ensuring its understanding and minimising technical terms.

Article 31. Authorisation of the information contained in the labelling and package leaflet.

1. The texts and other characteristics of the labelling and package leaflet are part of the application for the medicinal product and will require authorisation from the Spanish Agency for Medicinal Products and Health Products.

The modifications will also require prior authorisation from the Spanish Agency for Medicines and Health Products and will be resolved in accordance with the procedure laid down for the modifications of the authorisation.

2. The texts will be presented in Spanish at least. In addition, they may also be written in other languages.

Section 2. Medication Identification Guarantees: Labelling

Article 32. General requirements.

1. The labelling of the medicinal product shall include the detailed information in Annex III

2. The particulars to be provided on the labelling of medicinal products shall be clearly legible, clearly understandable and indelible. This data shall not mislead the nature of the product or the therapeutic properties thereof, to ensure its correct use or administration.

Article 33. Guarantees of authenticity and traceability of the labelling.

The outer packaging or, failing that, the primary packaging, shall incorporate the elements that allow the authentication of the verifiable product by automated means, as well as the information necessary to determine the traceability of the medicinal product from manufacture to its administration, including for this purpose the identification of the medicinal product, the batch of manufacture, and its expiry date, as set out in Annex III.

Article 34. Incorporation of symbols and graphic motifs.

1. The symbols listed in Annex III shall be included in the labelling.

2. The inclusion of other graphic reasons may be authorised which, being in conformity with the technical information sheet and not having an advertising character, are appropriate to facilitate the interpretation by the users of certain entries in Annex III.

Article 35. Obligation to declare certain excipients.

1. The labelling, in the declaration of the composition of the medicinal product, shall include the excipients of a compulsory declaration, the knowledge of which is necessary for the correct administration and use of the medicinal product.

2. The excipients of compulsory declaration shall be updated in accordance with scientific and technical progress and in accordance with the requirements of the European Union.

Article 36. Guarantee of correct identification: Name of the medicinal product.

1. The name with which the medicinal product is placed on the market shall meet the legally established requirements and in no case may mislead the therapeutic properties or the nature of the medicinal product.

The name of the veterinary medicinal product may consist of a name of fancy which cannot be confused with the common name, or the common or scientific name accompanied by a trade mark or the name of the holder of the the marketing authorization.

2. Such names shall be avoided which may lead to errors in the prescription or supply of names already existing in the pharmaceutical market, and the use of other previous names or prescription habits.

3. In general, and in accordance with the above two paragraphs, the names of medicinal products shall not be admissible where:

(a) Your prescription or dispensation may give rise to phonetic or orthographic confusion with that of another medicinal product or with animal health products, hygiene and management products, food additives for animal feed, feed, or with medical, cosmetic or food products.

(b) It has been used in a medicinal product for which the authorisation has been revoked and not more than five years after revocation, except that they have the same composition in active substances.

(c) Have an orthographic resemblance to a Spanish Official Denomination (DOE), with an International Common Denomination (INN) recommended or proposed by the World Health Organization (WHO), or with a usual common denomination or scientific.

(d) For medicinal products subject to prescription or medicinal product not subject to prescription, the name of which may not be the same or cause confusion with that of another medicinal product which does not have such a condition.

Section 3. Medication Information Guarantees: Package Leaflet

Article 37. General requirements of the package leaflet.

1. The package leaflet is the written information accompanying the medicine, which is addressed to the user. It identifies the holder of the authorization and the person responsible for the manufacture of the medicinal product, and, where appropriate, the name of the representative of the marketing authorisation holder, declares its composition and gives instructions for its administration, employment and conservation, as well as their adverse reactions, interactions, contraindications and other data as set out in Annex III, in order to propose their most correct use and compliance with the prescribed treatment, as well as measures to be taken in case of intoxication.

2. The package leaflet must be drawn up and designed in clear and comprehensible terms to enable users to act in an appropriate manner, where necessary with the help of healthcare professionals.

3. As a general rule, the package leaflet shall contain only the information concerning the medicinal product to which it relates. However, the Spanish Agency for Medicinal Products and Sanitary Products may, in certain circumstances, authorise the inclusion of information relating to different doses and available pharmaceutical forms of the same medicinal product.

4. The insertion of the package leaflet into all medicinal products is mandatory unless all the information required is included in the outer packaging or, failing that, in the immediate packaging.

5. The marketing authorisation holder shall ensure that, upon application by the associations concerned, and in the case of pet animals, the package leaflet shall be available in appropriate formats for blind or sighted persons. partial.

6. The Spanish Agency for Medicinal Products and Sanitary Products may decide that certain therapeutic indications are not included in the package leaflet or the technical fiche, in particular where the applicant for a generic veterinary medicinal product communicates that these indications are covered by the patent or data protection right at the time the generic medicinal product is authorised.

Article 38. Graphic motifs.

The inclusion in the prospectus of drawings and other graphic reasons may be authorised to supplement the written information of the prospectus, as well as other information, provided that, in accordance with the technical information sheet, for reasons of health education or for greater understanding for the user to whom they are directed, and do not meet criteria for the promotion or advertising of the medicinal product.

CHAPTER IV

Particular provisions for certain classes of medications

Section 1. Homoeopathic Medicines

Article 39. Classes of homeopathic veterinary medicines.

Homeopathic veterinary medicines may be:

(a) With approved therapeutic indication, the authorisation and registration procedure of which shall follow the procedure laid down in Chapter II, taking into account their homeopathic nature.

(b) No approved therapeutic indications, the authorisation and registration procedure of which shall be the special simplified homeopathic medicinal product, set up for this purpose by the Spanish Agency for Medicinal Products and Products Sanitary.

Article 40. Criteria to be met by homeopathic medicinal products to be registered under the special simplified procedure.

To obtain the simplified registration of a homeopathic veterinary medicinal product, without prejudice to the conditions laid down for pharmacologically active substances in Council Regulation 2377/1990 of 26 June 1990, the following conditions will have to be met:

(a) The route of administration described in the Spanish Royal Pharmacopoeia, in the European Pharmacopoeia or, failing that, in a pharmacopoeia used officially in a Member State of the European Union.

(b) Absence of special therapeutic indication on the label or in any information concerning the veterinary medicinal product.

c) Degree of dilution to ensure the safety of the medicinal product, in particular the medicinal product must not contain more than one part per 10,000 of the mother tincture.

Article 41. Special simplified registration procedure for homeopathic medicinal products.

1. The application for registration, which may cover the whole range of medicinal products obtained from the same homeopathic strain or strains, shall be accompanied by the following data and documents:

(a) Scientific name of homeopathic strains, or other name given in a pharmacopoeia, with reference to the different routes of administration, pharmaceutical forms and degrees of dilution to be recorded.

(b) Report describing the production and control of the strain or strains and justifying their homeopathic character, on the basis of an appropriate homeopathic bibliography; in the case of homeopathic veterinary medicinal products, which contain biological substances, a description of the measures taken to ensure the disposal of any pathogenic agent.

(c) Report on the manufacture and control of each of the pharmaceutical forms, together with a description of the dilution and dynamisation methods used.

(d) Authorisation to manufacture the medicinal products concerned.

e) A copy of the records or authorisations obtained, where appropriate, for the same medicinal products in other Member States.

f) One or more samples or models of the sales model to the public, of the medicines to be registered.

g) Information about the stability of the medicine.

h) A properly justified proposed wait time.

2. Where the simplified registration of a homeopathic medicinal product which has been registered as such in another Member State is requested, the mutual recognition procedure shall be applied, the application of which shall comply with the provisions of the Article 15.4. The European arbitration procedure shall not apply.

3. The maximum period for the notification of the decision of the procedure shall be 210 calendar days from the day following the date of submission of a valid application. Otherwise, the application shall be deemed to be rejected, with the result of the administrative and administrative disputes arising.

4. The criteria and rules of procedure laid down in Chapter II shall apply by analogy to the special simplified registration procedure for homeopathic veterinary medicinal products, which is not covered by that procedure, with the exception of: of the therapeutic effect test.

Article 42. Labelling of homeopathic medicinal products.

1. The labelling and, where appropriate, the package leaflet of homeopathic medicinal products with therapeutic indication, shall comply with the general provisions concerning the labelling and package leaflet referred to in this royal decree, and must be identified with the "homeopathic medicinal product for veterinary use".

2. The labelling and, where appropriate, the package leaflet of homeopathic medicinal products without approved therapeutic indication, should include, only and compulsorily, the following data:

(a) The scientific name of the strain or strains, followed by the degree of dilution, using the symbols of the pharmacopoeia used.

(b) The name and address of the marketing officer and, where applicable, the manufacturer.

c) The mode of administration and, if necessary, the route of administration.

d) The expiration date in clear form (month and year). In addition, medicinal products with reduced stability after reconstitution, dilution or opening, shall indicate the time of validity of the reconstituted preparation, diluted or after opening, and shall include a box for entry by the medicinal products. users.

e) The pharmaceutical form.

f) The contents of the sales model.

g) Special precautions for storage, where appropriate.

h) The species to which the medicinal product is intended.

i) Timeout, if any.

j) Special warnings if the medicine so requires.

k) The manufacturing batch number.

l) The record number.

m) Legend "Veterinary homeopathic medicine without approved therapeutic indications".

Section 2. Medical Gases

Article 43. Authorization to place medicinal gases on the market.

Medicinal gases are permitted in accordance with the provisions of this royal decree, taking into account the following specificities:

1. They must comply with the quality technical characteristics required by the Spanish Royal Pharmacopoeia, the European Pharmacopoeia or, failing that, in other official pharmacopoeias of the Member States of the European Union or of another country, to which the Ministry of Health and Consumer Affairs recognizes quality requirements equivalent to those referred to in the pharmacopoeas.

2. Medicinal gases containing the same component with qualities adjusted to different pharmacopoeias shall be considered as distinct products for the purposes of their marketing authorisation.

3. Any other medicinal gas intended to be used for therapeutic purposes, before being recognised by a pharmacopoeia as provided for in paragraph 1, shall be subject to the marketing authorization for the purposes of the assessment of its quality, safety and efficacy.

Article 44. Packaging and labelling.

1. The packaging and pipes used for the manufacture, distribution and marketing of medicinal gases shall be appropriate for the purpose for which they are intended and shall not affect the quality and/or stability of the content.

2. On the labelling of medicinal gases, the following data shall be recorded:

a) Logo or symbol of the medicinal gases.

b) Denomination.

c) Content in volume.

d) Qualitative and quantitative composition.

e) Technical specifications to be met.

(f) Name and address of the marketing authorisation holder and, where applicable, the name and address of the representative of the marketing authorisation holder.

g) Batch number.

h) Expiration date: month and year.

i) Conservation conditions.

j) Target species.

k) Prescription and dispensing conditions.

l) Supply and transport precautions.

m) Medicinal gases for veterinary use shall also include the national code.

n) The number of placing on the market, the mention "for veterinary use" and, where medicinal gas is to be administered to food-producing animals intended for human consumption, the waiting time even if this is null.

n) In specific cases, if deemed appropriate by the Health Administration, the inclusion of supplementary information may be required, accompanied by the product, in accordance with the provisions of this royal decree.

CHAPTER V

Obligations of the holder of the medicinal product

Article 45. Obligations of the holder of the authorisation.

The holder of an authorisation for a medicinal product is required to comply with the veterinary pharmacovigilance rules and, during the duration of the marketing authorisation:

(a) Observe the conditions under which the marketing authorisation was granted, in addition to the general obligations outlined in the legislation in force, as well as those of any modification of the conditions of the the authorisation laid down in the following Chapter, including those for manufacturing and control procedures. In no case will the modifications of the conditions of authorization be carried out without authorization.

b) Respect continuity in the service. The marketing authorisation holder has an obligation to supply the market for authorised medicinal products.

c) Keep the file permanently updated. The holder of the authorisation shall submit the periodic safety update reports, in order to keep the dossier up to date in the field of safety and in particular the information addressed to professionals. included in the technical information sheet of the medicinal product and the information in the package leaflet ensuring adequate understanding of the medicinal product, as well as those listed in Article 66.

d) Contribute to the appropriate knowledge of the medicinal product and promote its rational use. The holder of the authorisation is obliged to make available to the public, in particular healthcare professionals, the updated information on the technical information sheet of the medicinal product with the legally established information.

e) To collaborate in control programs, to ensure the adequacy of the products in the market and to report any possible withdrawal of lots from the market. The holder of the authorization of a medicinal product shall communicate to the Spanish Agency for Medicinal Products and Health Products, to the Autonomous Communities and to the authorities of all the countries where it has been distributed, with the appropriate speed to each case and setting out the grounds, any action taken to remove a lot from the market.

f) Obligation to bring the volume of sales and prescriptions. At the request of the Spanish Agency for Medicinal Products and Sanitary Products, in particular in the framework of pharmacovigilance and effective marketing, the marketing authorisation holder shall provide all data relating to the the sales volume of the veterinary medicinal product, as well as any information available to it in relation to the volume of the prescriptions.

(g) To deliver at the request of the competent authorities the substances in the quantities necessary to carry out checks to detect the presence of residues of veterinary medicinal products in animals food producers.

h) Any other legal or regulatory obligation established.

CHAPTER VI

Amendments to the conditions for authorization of medicines

Article 46. Modifications to the conditions of authorisation of the medicinal product.

1. Modifications to the conditions of authorisation of medicinal products are subject to prior authorisation by the Spanish Agency for Medicinal Products and Health Products in the following terms.

2. These modifications are classified into:

a) Minor modifications that are divided into IA-type modifications and IB-type modifications.

b) Major changes: type II.

3. Minor amendments are considered to be of minor importance as defined in Commission Regulation (EC) No 1084/2003 of 3 June 2003 concerning the examination of the amendments to the terms of the authorisations of the placing on the market of medicinal products for human use and veterinary medicinal products granted by the competent authority of a Member State.

4. Major modifications which are not typified as minor modifications are considered as minor in accordance with the provisions of the previous paragraph.

5. In accordance with the provisions of Commission Regulation (EC) No 1084/2003 of 3 June 2003, the conditions for the authorisation of a medicinal product shall not be considered to be the line extensions of the marketing authorisations for a medicinal product that will require a new marketing authorisation.

6. Amendments shall not be permitted during the processing of applications for marketing authorisation, except those imposed by the Spanish Agency for Medicinal Products and Sanitary Products and by the European Commission.

Article 47. Procedure for minor modifications.

1. The procedure for minor modifications shall be governed by the provisions of this royal decree and by the instructions on the subject approved by the Spanish Agency for Medicines and Health Products.

2. In applications for type IA modification, the Spanish Agency for Medicinal Products and Sanitary Products shall verify that it conforms to the group defined as IA and that the documentation submitted complies with the requirements for the modification concerned.

Within a maximum of 30 days, from the day following the filing of the application, the Spanish Agency for Medicinal Products and Sanitary Products shall notify the person concerned that his application has been accepted, and the latter shall proceed to its implementation. If not, the application shall be refused, by means of a reasoned decision. When the decisions are notified, the remedies shall be expressed in accordance with the provisions of the rules applicable to the case.

3. In the type IB amendments, the Spanish Agency for Medicines and Health Products shall verify that it conforms to the group defined as IB and that the documentation submitted complies with the requirements for the modification concerned.

Within 15 days, from the day following the filing of the application, the Spanish Agency for Medicines and Health Products shall inform the person concerned of his admission to the proceedings or, if necessary, request the subhealing of the request.

In case of admission to processing of the application, within 30 days from the day following the communication to the interested party, provided for in the previous paragraph, the Spanish Agency for Medicines and Sanitary Products notify the decision by authorizing the requested amendment, or a proposal for a decision to reject the application with the relevant hearing procedure, after which the reasoned decision shall be delivered and notified. When the decisions are notified, the resources to be taken against them shall be expressed in accordance with the rules applicable to the case.

Article 48. Procedure for major modifications.

1. The procedure for major modifications will be governed by the provisions of this royal decree and by the instructions on the subject approved by the Spanish Agency for Medicines and Health Products.

2. In major or type II changes, the Spanish Agency for Medicines and Health Products shall verify that the documentation submitted is in accordance with the modification to be implemented.

Within 15 days, from the day following the filing of the application, the Spanish Agency for Medicines and Health Products shall inform the person concerned of his admission to the proceedings or, if necessary, request the subhealing of the request.

In case of admission to processing of the application, within 90 days from the day following the communication to the person concerned, provided for in the previous paragraph, the Spanish Agency for Medicines and Health Products notify the resolution by authorizing or refusing the requested amendment, with an indication of the remedies against it.

3. At any time during the procedure preceding the decision, the Spanish Agency for Medicinal Products and Sanitary Products may request additional information or documentation from the person concerned, with the time limit set for the time being suspended. the resolution, for a period not exceeding 60 days.

Article 49. Special modifications.

1. Special amendments shall be considered for urgent amendments for reasons of safety and for amendments to the authorisation for reasons of general interest.

2. Urgent modifications for security reasons:

(a) Where new information is known to indicate an important risk to public health associated with the use of the medicinal product or has a relevant impact on the safety of the medicinal product, it shall result in a temporary change. and urgent information on the medicinal product which will affect in particular the following data from the technical information: indications, dosage, time-out, environmental impact, contraindications or warnings and precautions Special employment.

(b) If, for reasons of safety, the urgent modification of the conditions for the authorisation of a medicinal product is necessary, the holder shall request that amendment to the Spanish Agency for Medicinal Products and Products Sanitary, accompanying the following documentation:

1. Report on the detected risks that make modification necessary.

2. Proposal for amendment of the Summary of Product Characteristics and Package Leaflet.

3. Proposition of information to healthcare professionals.

4. Proposal for complementary actions, as well as any other information deemed necessary for the effective implementation of the modification.

If the Spanish Agency for Medicines and Health Products does not raise any objection within the next business day to the receipt of the information, urgent modifications for safety reasons will be considered accepted. on a provisional basis. The marketing authorisation holder shall request the modification of the technical information sheet within a period not exceeding the following 15 calendar days from the date of acceptance. The Spanish Agency for Medicinal Products and Sanitary Products shall establish the specific procedures to be followed in the pharmacovigilance rules.

(c) In the event that the urgent modification for safety reasons is imposed by the Spanish Agency for Medicines and Health Products, the holder shall be obliged to submit a request for modification in the terms of the to establish the Agency immediately and within a period not exceeding 15 calendar days following receipt of the Agency's notification. In any case, the procedure laid down in the pharmacovigilance rules shall be followed.

d) In the two previous assumptions, the deadline and terms of the information to healthcare professionals, as well as the effective implementation of the modification by the holder, including changes in the material packaging, will be agreed with the Spanish Agency for Medicines and Health Products.

e) In the case of products authorised under the mutual or decentralised recognition procedure, account shall be taken of the harmonisation mechanisms to be established for this purpose in the European Union through the guidelines. For products authorised in accordance with the centralised procedure, the provisions of Commission Regulation (EC) No 1084/2003 of 3 June 2003 and the guidelines implementing it shall be followed.

(f) The Spanish Agency for Medicines and Health Products shall communicate the urgent amendments for safety reasons to the health authorities of the autonomous communities, to the health professionals and, where appropriate, to the citizens, in accordance with the procedures laid down in the pharmacovigilance rules.

3. Modification of the authorisation for reasons of general interest:

(a) The Spanish Agency for Medicinal Products and Sanitary Products, for reasons of public interest, defence of public health or animal health, may modify the conditions for dispensing and/or prescribing a medicinal product.

(b) This procedure shall be processed with a hearing to the party concerned and the maximum period for the notification of the decision shall be 90 days. The opinion of the Committee for the Evaluation of Medicinal Products for Veterinary Use shall also be required.

(c) If the procedure is based on the safety of the medicinal product, the procedure shall be carried out in accordance with the provisions of the specific pharmacovigilance rules.

Article 50. Change of holder of the medicinal product.

1. The change of holder of the marketing authorisation for the medicinal product is subject to authorisation by the Spanish Agency for Medicinal Products and Sanitary Products.

2. Modifications to the authorisation of the medicinal product resulting from the change of holder shall be governed by the procedure laid down for the amendments.

CHAPTER VII

Procedures for suspending and revoking the authorization

Article 51. Causes of suspension, revocation and withdrawal from the market.

1. The Spanish Agency for Medicinal Products and Sanitary Products may agree to suspend or revoke the authorisation of a veterinary medicinal product when:

(a) the benefit-risk assessment of the veterinary medicinal product under the approved conditions of employment is not favourable, taking particular account of the animal health and animal welfare benefits, and the safety of consumers, where the authorisation concerns veterinary medicinal products for zootechnical use;

(b) the therapeutic effect of the veterinary medicinal product is missing in the treated animal species;

(c) the veterinary medicinal product does not have the declared qualitative and quantitative composition, or when quality assurance is not complied with or when the required quality controls are not carried out;

(d) the indicated waiting time is insufficient to ensure that the food products from the treated animal do not contain residues which may present hazards to the health of the consumer;

e) the veterinary medicinal product is presented for a prohibited use under other Community provisions;

(f) the information contained in the file is incorrect or does not comply with the rules of application in the matter;

(g) the controls carried out on the veterinary medicinal product and/or its components or the intermediate products of manufacture have not been carried out in accordance with the methods laid down in the marketing authorisation;

(h) there would be an amendment to the Annexes to Council Regulation (EEC) No 2377/1990 of 26 June 1990 and the marketing authorisation holder shall not take the necessary measures to amend the authorisation. for the placing on the market within a maximum period of 60 days following the publication of that amendment in the Official Journal of the European Union;

i) for non-compliance with the rules on labelling and package leaflet;

j) for any other cause that poses a foreseeable risk to the health or safety of persons, animals or the environment.

2. Without prejudice to Article 99 of Law No 29/2006 of 26 July, the Spanish Agency for Medicinal Products and Sanitary Products may suspend the marketing of medicinal products which correspond to them, where appropriate, on the market. causes referred to in points (a), (b), (c), (d) and (g) of the previous paragraph.

3. However, where a Community regulatory framework is still in the process of adoption, the Spanish Agency for Medicinal Products and Sanitary Products may refuse the authorisation of a veterinary medicinal product if such a measure is necessary to ensure the protection of public health, consumers or animal health.

Article 52. Procedure for suspension and revocation of trade.

1. The Spanish Agency for Medicinal Products and Sanitary Products may suspend or revoke the authorisation of a medicinal product for the reasons provided for in the previous Article, subject to a report by the competent committee. In the case of suspension of the marketing authorisation, the marketing authorisation shall not interrupt the period laid down in Article 27 (3) and (4

.

2. The procedure shall be initiated by agreement of initiation and hearing of the person concerned, and a decision shall be made to notify the person concerned within the maximum period of six months, indicating the resources.

3. The Spanish Agency for Medicinal Products and Sanitary Products shall notify the European Medicines Agency of the resolutions of suspension, revocation and modification of the conditions of the authorisation which are considered to be relevant.

Article 53. Suspension and revocation procedure at the instance of a party.

1. Where the holder of an authorisation for a medicinal product intends to suspend or cease placing on the market, he shall notify the Spanish Agency for Medicinal Products and Sanitary Products at least two months before the date on which he has To withdraw the product from the market, motivating that request. In the case of suspension of the marketing authorisation, the marketing authorisation shall not interrupt the period laid down in Article 27 (3) and (4

.

2. Notwithstanding the foregoing, where health or health concerns are present, or therapeutic vacuum may arise, the Spanish Agency for Medicinal Products and Sanitary Products shall maintain the validity of the authorization and shall require the placing on the market. effect of the medicinal product.

CHAPTER VIII

Community Procedures

Article 54. Definitions and general requirements of Community procedures.

1. Mutual recognition means the Community procedure laid down for the granting of a marketing authorisation for a medicinal product in more than one Member State where the medicinal product has already been evaluated and authorised in one of the Member States. Member States.

2. Decentralised, the Community procedure laid down for the granting of a marketing authorisation for a medicinal product in more than one Member State where the medicinal product does not have an authorisation in any Member State Member of the European Union at the time of application.

3. Both procedures require the applicant to submit an application based on an identical dossier in all Member States involved in the procedure. The file shall include the information and documents referred to in Section 1 of Chapter II.

The submitted documents shall include a list of the Member States concerned by the application.

Article 55. Mutual recognition procedure.

1. Where the holder of a medicinal product already authorised in Spain intends to apply for authorisation in another Member State or other Member State, Spain may act as a reference Member State in the procedure.

2. In the event that Spain acts as a reference Member State, the marketing authorisation holder shall request the Spanish Agency for Medicinal Products and Sanitary Products to draw up a report on the evaluation of the medicinal product, or update the existing assessment report for that drug.

3. The Spanish Agency for Medicinal Products and Health Products shall draw up or update this report within 90 calendar days of receipt of a valid application.

4. The assessment report, as well as the technical information sheet of the authorised medicinal product, the labelling and the package leaflet, shall be sent to the Member States concerned and to the applicant.

5. Within 90 days of receipt of the documents referred to in the preceding paragraph, the Member States concerned shall approve the documents submitted by the Spanish Agency for Medicinal Products and Health Products, informing them of their acceptance. The Agency shall endeavour to reach the general agreement and finalise the procedure and inform the applicant accordingly. Within 30 days, all Member States involved must resolve in accordance with the general agreement.

6. When an application for authorization to place an authorised medicinal product on the market in another Member State is submitted to the Spanish Agency for Medicinal Products and Sanitary Products, the mutual recognition procedure shall apply to it, It is understood that Spain is a Member State concerned in the proceedings. In this case, the procedure described above shall apply from the documentation submitted by the Member State acting as a reference Member State, in accordance with the provisions of the previous paragraph.

Article 56. Decentralised procedure.

1. Where it is intended to obtain a marketing authorisation for a medicinal product in more than one Member State, the applicant shall request one of them to act as a reference Member State.

2. When Spain acts as a reference Member State, the Spanish Agency for Medicinal Products and Sanitary Products will prepare a draft assessment report, a draft technical fiche and a draft labelling and package leaflet, within 120 days. natural days from the receipt of a valid application, and shall send them to the other Member States concerned and to the applicant.

3. Within 90 days of receipt of the documents referred to in the preceding paragraph, the Member States concerned shall approve the documents submitted by the Spanish Agency for Medicinal Products and Health Products, informing them of their acceptance. The Agency shall endeavour to reach the general agreement and finalise the procedure and inform the applicant accordingly. Within 30 days, all Member States involved shall be required to resolve in accordance with the general agreement.

4. Where in a decentralised procedure it is another State acting as a reference Member State, Spain being involved as a State concerned, the Spanish Agency for Medicinal Products and Health Products shall apply the procedure described above. previously, on the basis of the documentation submitted by the reference Member State, in accordance with the provisions of the previous paragraph.

Article 57. Discrepancy in arbitration decisions and procedures.

1. Where, in a Community procedure, Spain, as a Member State concerned, is unable to approve within the period of 90 calendar days referred to in Articles 55.5 and 56.3 the assessment report, the summary of the product characteristics, the labelling and the package leaflet, considering that there is a serious potential risk to public health, will motivate its decision in a detailed manner and shall communicate its reasons to the Member State of reference and the other Member States concerned.

2. In the event that Spain is a reference Member State and receives a communication of disagreement from another Member State, the Spanish Agency for Medicines and Health Products shall communicate the disagreement to the other Member States concerned and to the applicant.

It shall immediately communicate the reasons for disagreement to the Coordination Group, to examine issues relating to the marketing authorisation for medicinal products in two or more Member States.

3. All Member States involved in the procedure shall endeavour to agree within the framework of the coordination group on the measures to be taken. They shall provide the applicant with the possibility to issue orally or in writing.

If, within 60 days of the communication to the Coordination Group, the Member States reach an agreement, the Member State of reference, where appropriate, the Spanish Agency for Medicinal Products and Health Products, shall endeavour to achieve the general agreement and terminate the procedure and inform the applicant accordingly.

4. If, within the period laid down in the previous paragraph, the Member States do not reach an agreement, the Member State of reference, as the case may be, the Spanish Agency for Medicinal Products and Sanitary Products, shall inform the European Medicines Agency with the the purpose of initiating the arbitration procedure by referring a detailed description of the questions on which the Member States have not been able to reach an agreement and the reasons for their disagreement. A copy of this information shall be sent to the applicant, which shall forward a copy of the dossier to the European Medicines Agency without delay.

5. However, in the event that the Spanish Agency for Medicinal Products and Sanitary Products has approved the assessment report, the technical information sheet, the labelling and the package leaflet, it may, at the request of the applicant, authorise the placing on the market of of the medicinal product prior to the decision of the European Commission. In this case the authorisation shall be granted subject to the outcome of the arbitration procedure.

Article 58. Harmonisation of Community authorisations.

1. Where the same medicinal product has been subject to different applications for authorisation and the Member States have taken dissenting decisions in respect of the authorisation, suspension or revocation, Spain, any Member State, the Commission, the applicant or the holder of the authorisation may address the Committee for Veterinary Medicinal Products of the European Medicines Agency in order to apply the arbitration procedure.

2. In order to promote the harmonisation of medicinal products authorised in the European Union, the Spanish Agency for Medicinal Products and Sanitary Products shall forward annually to the Coordination Group a list of the medicinal products for which it considers that harmonised technical sheets should be drawn up. This coordination group shall take into account the various proposals submitted by all Member States and shall send a list to the European Commission for harmonisation.

Article 59. Decisions of Community interest.

1. In specific cases where the interests of the European Union are at stake, any Member State, as the case may be, the Spanish Agency for Medicinal Products and Sanitary Products, the Commission, the applicant or the holder of the authorisation shall use the Committee for Veterinary Medicinal Products of the European Medicines Agency, for the application of the arbitration procedure, before a decision is taken on an application for authorisation, on a suspension or revocation of an authorisation or a any other changes, in particular for cases relating to new information safety based on pharmacovigilance of the medicinal product. Such request shall be accompanied by all available information.

Of the above, the applicant or the holder of the authorisation shall be informed, where the Commission or any Member State has recourse to the Committee for Veterinary Medicinal Products of the European Medicines Agency.

2. Where the use of the Committee for Veterinary Medicinal Products of the European Medicines Agency relates to a number of medicinal products or a therapeutic category, the European Medicines Agency may limit the procedure to a specific part of the the authorization.

3. Where the Spanish Agency for Medicinal Products and Sanitary Products considers that the modification of the terms of a marketing authorisation granted in accordance with this Chapter, or its suspension or withdrawal, are necessary for to protect public health, it shall without delay submit the matter to the European Medicines Agency for the adoption of a Community decision.

4. In exceptional cases, where urgent action is essential to protect public health, and until a final decision is taken, the Spanish Agency for Medicines and Health Products may suspend marketing and use in Spain of the medicinal product concerned. This measure shall be communicated to the Commission and to the other Member States the following day.

CHAPTER IX

Veterinary pharmacovigilance

Article 60. Spanish Pharmacovigilance System for Veterinary Medicinal Products.

1. The Spanish Pharmacovigilance System for Veterinary Medicinal Products shall meet the relevant information for the supervision of veterinary medicinal products and any suspected adverse reactions in animals and humans, and shall carry out the scientific evaluation of such information.

2. This information shall be examined taking into account the available data on the sale and prescription of veterinary medicinal products.

3. The Spanish Pharmacovigilance Pharmacovigilance System for veterinary medicinal products shall take into account any information available on the lack of expected efficacy, the non-contemplated use, the investigations into the validity of the withdrawal period and the possible environmental problems arising from the use of the veterinary medicinal product, interpreted in accordance with the guidelines laid down in the field of the European Union which may have an impact on the assessment of their benefits and risks. In order to harmonise the collection and management of information, the Spanish Agency for Medicines and Health Products may:

(a) Establish specific requirements for veterinarians and other healthcare professionals, especially in relation to the reporting of suspected serious or unexpected adverse reactions in animals and suspected reactions adverse in people.

b) Develop specific guidance to the marketing authorisation holders on the collection of data, their verification and reporting.

Article 61. Sources of information in veterinary pharmacovigilance.

Information about the risks associated with veterinary medicines can come from the following sources:

a) Notification of suspected adverse reactions by veterinarians, physicians, pharmacists and other healthcare professionals.

b) Notification of suspected adverse reactions by the marketing authorisation holders.

c) Notification of suspected adverse reactions by animal owners or livestock owners.

d) Regular security reports.

e) Post-marketing authorization studies.

f) Health databases.

g) Pre-clinical animal testing reports and reports from clinical trials of a veterinary medicinal product or an active substance.

(h) Information related to the manufacture, preservation, distribution, prescription, dispensing, sale, administration and habits of use in animals of a veterinary medicinal product or active substance.

i) Publications of the scientific literature.

(j) Other sources of information, such as those relating to the misuse and abuse of medicinal products, which may have an impact on the assessment of the benefits and risks of veterinary medicinal products.

k) The Ministry of the Environment, and the Rural and Marine Environment, as well as other national and international authorities and agencies.

Article 62. Agents of the Spanish Pharmacovigilance System for Veterinary Medicinal Products.

1. The Spanish Pharmacovigilance System for Veterinary Medicinal Products is composed of:

a) The Spanish Agency for Medicines and Health Products.

b) The Autonomous Communities.

c) Healthcare professionals.

2. The Technical Committee of the Spanish Pharmacovigilance Pharmacovigilance System, as a collegiate body composed of representatives of the Spanish Agency for Medicines and Health Products, the Ministry of the Environment, and the Rural and Marino and the Autonomous Communities shall unify the operating criteria and evaluate the signals detected by the Spanish Pharmacovigilance System for Veterinary Medicinal Products.

By ministerial order the composition, functions and functioning of that committee will be developed in accordance with the provisions of the law of the collegiate bodies in Law 30/1992, of 26 November, of the Legal Regime of the Public administrations and the Common Administrative Procedure.

Article 63. Functions of the Spanish Agency for Medicines and Health Products.

These are the functions of the Spanish Agency for Medicines and Health Products:

a) Plan, coordinate, evaluate and develop the Spanish Pharmacovigilance System for Veterinary Medicinal Products, as well as the tasks of its Technical Committee, in accordance with the "Good Pharmacovigilance Practices of the Spanish System" Pharmacovigilance for veterinary medicinal products " to be drawn up by the Technical Committee and published by the Spanish Agency for Medicinal Products and Health Products.

b) To participate, together with the European Medicines Agency, the European Commission and the other Member States, in the establishment of a computer network to exchange information on pharmacovigilance of medicinal products veterinarians.

c) Adopt appropriate measures to encourage the reporting of any suspected adverse reactions to a veterinary medicinal product.

d) Develop and manage the database of the Spanish Pharmacovigilance Pharmacovigilance System, which enables electronic access to the information collected by said System, ensuring at all times its availability and update, monitoring their security and ensuring data confidentiality and integrity during data transfer processes.

e) Acting as interlocutor of the Spanish Pharmacovigilance System for Veterinary Medicinal Products with the holders of marketing authorisations for medicinal products, healthcare professionals and, where appropriate, with the owners of animals and livestock farmers.

(f) Make available to the marketing authorisation holder immediately, and within a period not exceeding 15 calendar days following notification, reports of suspected serious adverse reactions in the animals and adverse reactions in persons that have occurred in Spain. Any other veterinary pharmacovigilance information not referred to in the preceding subparagraph shall be expressly requested by the person concerned.

g) To transmit to the European Medicines Agency and to the Member States immediately, and in any event within 15 calendar days of receipt, notifications of suspected adverse reactions. serious animals and persons, which have occurred in Spain. Such communication shall be carried out through the data processing network which the European Medicines Agency shall establish in collaboration with the Member States and the Commission.

(h) To provide for the procedures arising from the pharmacovigilance of medicinal products when appropriate to the General Administration of the State.

i) Conduct pharmacepizootiological studies and other research to evaluate the efficacy and safety profiles of veterinary medicinal products.

j) Put in place the necessary strategies to prevent, as far as possible, the risks associated with the use of veterinary medicinal products already on the market.

(k) Manage the funds for veterinary pharmacovigilance activities, the functioning of the communication networks and the supervision of the market that is of their competence, which will be under their permanent control with the purpose of ensuring their independence.

l) Establish the tools necessary to inform the practitioners of the relevant risks associated with the use of veterinary medicinal products.

m) The provisions of this matter by Royal Decree 520/1999, of 26 March, for which the Statute of the Spanish Medicines Agency is approved.

n) Any other function which may be necessary in the field of veterinary pharmacovigilance and which must be exercised by the Spanish Agency for Medicinal Products and Health Products.

Article 64. Participation of the Autonomous Communities in the Spanish Pharmacovigilance System for Veterinary Medicinal Products.

1. The competent bodies of the Autonomous Communities are responsible for collaborating with the Spanish Agency for Medicines and Health Products in the promotion of suspected adverse reactions in their territorial scope. in accordance with the criteria to be established by the Spanish Agency for Medicines and Health Products.

2. They shall also record in the database of the Spanish Pharmacovigilance Pharmacovigilance System, within the maximum period of 20 calendar days from their receipt, the notifications of suspected adverse reactions which they would have received. knowledge, except in the case of suspected serious adverse reactions and reactions in persons, who must be registered within the maximum period of 10 calendar days from their receipt.

3. Collaborate on the veterinary pharmacovigilance activities that are required.

Article 65. Obligations of healthcare professionals.

Veterinarians, physicians, pharmacists, and other healthcare professionals have an obligation to:

(a) Collaborate in the Spanish Pharmacovigilance System for veterinary medicinal products, especially in the case of serious or unexpected adverse reactions or where such communication is a condition in the authorisation

(a)

(b) Notify any suspected adverse reaction of which they are aware during their normal practice and send it as quickly as possible to the Spanish Agency for Medicines and Health Products or to the holder of the product marketing authorization, using the form that was set.

c) Keep clinical documentation of suspected adverse drug reactions, in order to complete or follow up, if necessary.

d) Cooperate with the technicians of the Spanish Pharmacovigilance System of Veterinary Medicinal Products, providing the necessary information that they request to extend or complete the information about the presumed reaction adverse.

e) Staying informed about the efficacy and safety data of medications that are usually prescribed, dispensed, or administered, as the case may be.

f) Collaborate with the pharmacovigilance officers of the marketing authorisation holders, providing the information requested to them, for further notification to the Spanish Pharmacovigilance System of veterinary medicinal products.

g) To collaborate with the Spanish Agency for Medicines and Health Products, as experts, in the evaluation of the problems of efficacy and safety of the drugs.

Article 66. Obligations of the holders of the marketing authorisations.

The holder of the marketing authorisation for a veterinary medicinal product:

(a) Keep detailed records of all suspected adverse reactions occurring within the European Union or in a third country. Unless technical impossibility, these reactions shall be communicated in the form of electronic notification and in accordance with the guidelines laid down.

(b) shall have at its disposal, on a permanent and continuous basis, a suitably qualified person responsible for veterinary pharmacovigilance, who shall reside in the European Union.

(c) Register and electronically notify the Spanish Agency of Medicines and Health Products promptly, and within a period of no more than 15 days after receipt of the information, any suspected reaction serious adverse event in animals and any suspected adverse reactions in persons in Spain which have been communicated to it in relation to the use of the veterinary medicinal product.

You will also record and electronically notify the Spanish Agency of Medicines and Health Products promptly, and at the latest within 15 days of receipt of the information, any other alleged serious adverse reaction in animals and any suspected adverse reactions in persons occurring in Spain related to the use of the veterinary medicinal product, which may reasonably be presumed to be aware of them.

d) Use internationally accepted veterinary medical terminology for the transmission of reports on suspected adverse reactions, in accordance with the guidelines established by the Spanish Agency of Medicines and Healthcare products.

e) It shall ensure that all suspected serious and unexpected adverse reactions in animals, adverse reactions in persons and suspicions of transmissions of an infectious agent by a veterinary medicinal product occurring in the territory of a third country, shall be notified promptly and, at the latest within 15 days of receipt of the information, electronically to the Spanish Agency for Medicinal Products and Sanitary Products. In the event that it is communicated in the European standard electronic format to the European Medicines Agency, it shall be considered as notified to the Spanish Agency for Medicines and Health Products.

(f) to ensure, in the case of medicinal products whose reference Member State is Spain, that they have been authorised by the mutual recognition procedure, or decentralised, or which have been the subject of a Community decision, all suspected serious adverse reactions in animals and adverse reactions in persons occurring outside Spain, but in the territory of the European Union are reported in format and at the intervals indicated by the Spanish Agency of Medicines and Health Products for analysis and monitoring of these adverse reactions for the whole of the European Union. Where the notifications referred to in this paragraph are made in the electronic format, any adverse reaction sent to the database of the European Medicines Agency or the competent authority shall be deemed to have been notified to Spain. of the Member State concerned, if it occurs within the European Union, the specific notification to Spain is not necessary.

(g) Unless other requirements have been established as a condition for the granting of the marketing authorisation, or are subsequently established, notifications of all adverse reactions shall be submitted to the the Spanish Agency for Medicinal Products and Sanitary Products in the form of a periodic safety report, immediately upon request, or at least every six months from the marketing authorisation and until its placing on the market. Periodic safety reports shall also be submitted immediately upon request or at least every six months during the first two years following the initial and annual marketing during the two years. next. From that point on, the reports shall be submitted every three years, or as soon as they are requested. Periodic safety reports shall be accompanied by a scientific assessment of the benefit/risk ratio of the veterinary medicinal product. Periodic safety reports shall be submitted in accordance with the guidelines of Volume 9 of the Rules on Medicinal Products in the European Union.

(h) Following the granting of a marketing authorisation, the holder may request the modification of the periods referred to in point (g) of this Article, in accordance with the procedure laid down in the rules (a) Community rules on changes to the conditions for the authorisation of a medicinal product.

i) You may not communicate to the public data on pharmacovigilance issues relating to your veterinary medicinal product without prior to or at the same time as the Spanish Agency for Medicinal Products and Health Products. In any event, the marketing authorisation holder shall ensure that the information is presented in an objective manner and is not misleading.

j) Track the global scientific literature in order to identify the published cases of adverse reactions where there is a reasonable suspicion that the causative is an active substance in a medicinal product of whose marketing authorisation in Spain is a holder. These cases shall be reported in accordance with the criteria specified in this Article.

k) Carry out, where necessary, post-authorisation supervision studies to confirm, quantify or characterize potential risks, or to provide new scientific information on the relationship benefit/risk of authorised veterinary medicinal products in Spain.

l) Carry out a continuous assessment of the benefit/risk ratio of the veterinary medicinal products authorised in Spain and immediately communicate to the Spanish Agency of the Medicines and Sanitary Products new information that may influence the overall assessment of the benefit/risk ratio or may require modification of the technical sheet, package leaflet or both.

m) To inform healthcare professionals of new data concerning aspects of efficacy or safety of a medicinal product, when at the discretion of the Spanish Agency for Medicines and Health Products it is considered necessary. The text must be agreed in advance with the Spanish Agency for Medicines and Health Products, indicating the nature of the information contained in it.

Article 67. Person responsible for veterinary pharmacovigilance of the marketing authorisation holder.

This qualified person, as provided for in Article 66.b), shall be responsible for:

(a) Create and maintain a system for collecting and dealing with information about suspected adverse reactions identified to the company's staff, including their representatives, in order to make it accessible at least in a place in the European Union.

b) Prepare the required reports for the competent authorities.

c) Ensure that a rapid and complete response to any request for additional information from the Spanish Agency for Medicines and Health Products is required to be able to assess the benefits and risks of a medicinal product veterinary medicinal product, including information concerning the volume of sales or prescriptions of the veterinary medicinal product concerned.

(d) To provide the Spanish Agency for Medicinal Products and Health Products with any other information of interest for the assessment of the benefits and risks associated with a veterinary medicinal product, including appropriate information on post-marketing authorisation studies.

Article 68. Amendments to the conditions of ex officio authorization.

1. The Spanish Agency for Medicinal Products and Sanitary Products may amend and restrict the conditions for the authorisation of a veterinary medicinal product concerning its composition, indications, timeouts or information on adverse reactions or establish a reservation under the conditions of authorisation, where necessary for reasons of public interest or for the protection of the health or safety of persons or animals.

2. The Spanish Agency for Medicinal Products and Sanitary Products, acting in advance of the initiation of the procedure for the modification of the conditions of the marketing authorization, shall request an opinion from the Medicinal products for Veterinary Use.

You shall also request the marketing authorisation holder for the reports, documents or data relating to certain aspects relating to the conditions of authorisation of the veterinary medicinal product.

3. The Spanish Agency for Medicinal Products and Health Products, in the light of the report of the Committee on the Safety of Medicinal Products for Veterinary Use and the documentation submitted by the holder, shall initiate the appropriate procedure with hearing the person concerned, shall give a decision indicating the resources and shall notify the person concerned. The duration of the procedure shall be six months.

4. The holder of the marketing authorisation shall request the Spanish Agency for Medicinal Products and Sanitary Products, the modifications laid down in the resolution.

Article 69. Communication to the Ministry of the Environment, and the Rural and Marine Environment, to the Autonomous Communities, health professionals and citizens.

1. The Spanish Agency for Medicines and Health Products shall inform the Ministry of the Environment, and the Rural and Marine Environment, the Autonomous Communities and other public or private bodies and organisations responsible for the adoption of measures which, due to their relevance, should be made known to healthcare professionals.

The autonomous communities will disseminate this information among healthcare professionals who, both in the public and private sectors, exercise their activity in their territorial scope.

2. The Spanish Agency for Medicines and Health Products and the Autonomous Communities will provide citizens with information on the risks of medicinal products that may have relevant health implications.

Article 70. Post-authorisation studies.

1. Post-authorisation studies shall be intended to supplement the information obtained during the clinical development of veterinary medicinal products prior to their marketing authorisation. Post-authorisation studies shall not be planned, carried out or financed in order to promote the prescription of veterinary medicinal products.

2. Post-authorisation studies shall be carried out in accordance with the conditions laid down by the Spanish Agency for Medicinal Products and Health Products.

3. The Spanish Agency for Medicines and Health Products will keep a register of post-authorisation studies. To this end, the study promoter should send a copy of the study protocol to the Spanish Agency for Medicines and Health Products, communicate the effective start of the study and report the follow-up reports and the final report.

Additional disposition first. Exemption from the requirement of veterinary prescription for medicinal products intended for food-producing animals.

All veterinary medicinal products intended for food-producing animals for human consumption shall be subject to veterinary prescription from the entry into force of this royal decree. For veterinary medicinal products which satisfy the conditions for exemption from this obligation, provided for in Article 24, they must apply for a corresponding application for an amendment to the conditions of authorization in which the medicinal product complies with these conditions.

Additional provision second. Access by the Ministry of the Environment, and the Rural and Marine Environment to the databases of the Spanish Agency for Medicines and Health Products.

The Spanish Agency for Medicines and Health Products will facilitate access to the Ministry of the Environment, and the Rural and Marine Environment to its databases related to the procedures for authorization of medicinal products. veterinarians.

Additional provision third. Availability of medicines.

The Ministry of the Environment, and the Rural and Marine Environment and the Ministry of Health and Consumer Affairs, in the field of their respective competencies, will promote the availability of veterinary medicinal products for all livestock species. food production, in particular through actions aimed at promoting, promoting and supporting research, experimentation, development, registration and marketing of food.

To this end, the Committee for the Availability of Veterinary Medicinal Products is hereby established as a collegiate body, under the Spanish Agency for Medicines and Health Products, for the assessment, review and assessment of the availability of veterinary medicinal products.

By ministerial order the composition, functions and functioning of that committee will be developed in accordance with the provisions of the law of the collegiate bodies in Law 30/1992, of 26 November, of the Legal Regime of the Public administrations and the Common Administrative Procedure.

Additional provision fourth. National code and traceability of veterinary medicinal products.

Within one year of the entry into force of this royal decree, all the medicines will have to be granted to the corresponding National Code. For medicinal products already authorised, they shall be granted on their own initiative in accordance with the timetable laid down by the Spanish Agency for Medicinal Products and Health Products.

Within three years of the entry into force of this royal decree, the codification system shall be operational to enable the information collected in Article 33 to be recovered by electronic means.

First transient disposition. Adequacy of the renewals of the marketing authorisations.

The veterinary medicinal products authorized prior to the date of entry into force of this royal decree, to grant them indefinite authorization and to apply the system of renewal of the authorizations of the The marketing authorisation provided for in this royal decree must be renewed, in accordance with the instructions for ordering the Spanish Agency for Medicines and Health Products.

Second transient disposition. Adequacy of the technical information sheet and the packaging material.

1. The technical information sheet and the packaging material of the veterinary medicinal products authorized prior to the entry into force of this royal decree will be adapted to the information and structures in the previewed one, according to the stipulated for renewal of the marketing authorization.

2. Applications for marketing authorization and requests for modification of the conditions of authorization affecting the information on the technical information sheet and the packaging material, which are in the process of being processed at the time of the The entry into force of this royal decree, must be adapted to the information and structures in the previewed, before the granting of the marketing authorization.

Transitional provision third. Adequacy of conditioning material in veterinary medicinal products intended for food-producing animals for human consumption.

Marketing authorisation holders for veterinary medicinal products intended for food-producing animals for human consumption must, within one year of the entry into force of this royal decree, incorporate in the conditioning material the legend "of veterinary medicinal product use subject to veterinary prescription".

Single repeal provision. Regulatory repeal.

The following provisions are repealed:

(a) Royal Decree 109/1995 of 27 January 1995 on veterinary medicinal products, Article 5 of Title I; Article 8 of Chapter I of Title II, with the exception of definitions 10, 11, 12, 14, 16, 17 and 18; Chapters III, IV, Section 4. of Chapter VI and Chapter VIII of Title II; Articles 72 and 73 of Chapter I of Title VI; Article 105 of Chapter I and Chapter III of Title VII, as well as Annex I.

(b) Royal Decree 110/1995 of 27 January establishing rules on homeopathic veterinary medicinal products.

c) Royal Decree 1800/2003 of 26 December on the regulation of medicinal gases, with the exception of Article 4 (2) and (3), and Chapter III, in which it does not contravene this royal decree.

Final disposition first. Legislation on pharmaceutical products.

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. Incorporation of European Union law.

1. This royal decree incorporates into Spanish law Directive 2001 /82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products, as amended by the Directive 2004 /28/EC of the European Parliament and of the Council of 31 March 2004, with the exception of Titles IV, VI and partially Titles VIII and X.

2. Commission Directive 2006 /130/EC of 11 December 2006 implementing Directive 2001 /82/EC of the European Parliament and of the Council as regards the establishment of criteria for the derogation from the requirement of veterinary prescription for certain veterinary medicinal products intended for food-producing animals.

Final disposition third. Regulatory development.

1. The Ministers for Health and Consumer Affairs and the Environment, and the Rural and Marine Environment are empowered to lay down the provisions necessary for the implementation and development of this royal decree, as well as to update its annexes in accordance with the progress of the scientific and technical knowledge, in accordance with the guidelines and guidelines of the European Union.

2. The Ministers for Health and Consumer Affairs and the Environment, and the Rural and Marine Environment, are empowered to lay down the provisions necessary for the development of Article 6.6 of this royal decree as regards the requirements of applications for medicines intended for aquarium fish, birds of particular houses, messenger pigeons, terrarium animals, small rodents, ferrets and rabbits used only as pet animals and not subject to veterinary prescription as well as the specific requirements in the conditioning material for these medicinal products.

Final disposition fourth. Entry into force.

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

Given in Madrid, July 18, 2008.

JOHN CARLOS R.

The First Vice President of the Government and Minister of the Presidency,

MARIA TERESA FERNANDEZ DE LA VEGA SANZ

ANNEX I

FILE STRUCTURE

Analytical, safety, preclinical and clinical standards and protocols in the field of testing of veterinary medicinal products

Introduction

The data and documents accompanying the applications for marketing authorisation submitted pursuant to Articles 6 and 7 shall be submitted in compliance with the requirements set out in this Annex and taking into account the requirements set out in this Annex. Guidelines for the "Explanatory note for applicants for marketing authorisations for veterinary medicinal products in the Member States of the European Community", published by the Commission in Volume V (Veterinary Medicinal Products) Rules on medicinal products in the European Community.

When drawing up the dossier for the application for marketing authorisation, applicants shall take into account the Community guidelines on the quality, safety and efficacy of veterinary medicinal products, published by the Commission in the European Community rules on medicinal products.

All useful information for the evaluation of the medicinal product must be included in the application, whether favourable to the product or not. In particular, all relevant data shall be provided on any incomplete or abandoned test or test in relation to the medicinal product. Furthermore, once the marketing authorisation has been granted, any information relevant to the assessment of risks and benefits not included in the marketing authorisation should be sent immediately to the Spanish Agency for Medicinal Products and Sanitary Products. original request.

Member States shall ensure that all animal experiments are carried out in accordance with Royal Decree 1201/2005 of 10 October on the protection of animals used for experimental and other purposes. scientists

The provisions of Title I of this Annex shall apply to veterinary medicinal products which are not immunological.

The provisions of Title II of this Annex shall apply to immunological veterinary medicinal products.

TITLE I

Requirements for veterinary medicinal products other than immunological veterinary medicinal products

PART 1

Case Summary

A. Administrative data

The veterinary medicinal product which is the subject of the application must be identified by name and the name of the active substance or principle, together with the indications, pharmaceutical form, method and route of administration and description of the final sales presentation of the product.

The name and address of the applicant shall be entered, together with the name and address of the manufacturers and sites involved in the various stages of production (including the manufacturer of the finished product and the manufacturer). manufacturer or manufacturers of the active substance (s)), as well as, where appropriate, the name and address of the importer.

The applicant shall communicate the number and title of the volumes of documentation it sends in support of the application and shall indicate, where appropriate, the samples it attaches.

A document certifying that the manufacturer is authorised to manufacture the veterinary medicinal product concerned shall be attached to the administrative data, the list of the countries in which the authorisation has been granted, copies of all summaries of the product characteristics, approved by the Member States and the list of countries where the application was submitted.

B. Technical tab (summary of features

of the product) and conditioning material

The applicant will propose a summary of the product characteristics. In addition, the applicant shall provide one or more samples or mock-ups of the sale of the veterinary medicinal product, together with a package leaflet, where necessary.

C. Expert reports

The documentation concerning the analytical tests, the toxicological tests, the residue studies and the clinical tests shall contain the relevant expert reports.

Each expert report shall consist of a critical assessment of the various tests or trials carried out in accordance with this royal decree, and shall demonstrate all relevant data for the assessment. The expert shall indicate whether, in his opinion, the product concerned provides sufficient guarantees as regards quality, safety and efficacy. An objective summary will not be sufficient.

All important data will be summarized in an appendix to the expert's report, whenever possible in the form of tables or charts. The expert report and summaries shall contain precise references to the information contained in the main documentation.

Each expert report will be prepared by a person with due training and experience. The expert will sign and date and attach a brief overview of the qualifications, training and professional experience of the expert. The professional relationship between the expert and the applicant shall be recorded.

PART 2

Analytical (physico-chemical, biological or microbiological) tests of veterinary medicinal products other than immunological veterinary medicinal products

All analytical procedures will be in line with the most recent scientific developments, and will be validated procedures; the results of the validation studies will be provided.

All analytical procedures shall be described in detail in order to enable them to be reproduced in the control tests carried out at the request of the competent authorities; it shall also be described with the details of any special equipment or equipment which may be used, accompanied by the description, where possible, of schemes. The formula of the reagents shall be supplemented, if appropriate, by the method of preparation. In the case of analytical procedures included in the European Pharmacopoeia or in the pharmacopoeia of a Member State, this description may be replaced by a precise reference to the pharmacopoeia concerned.

A. Qualitative and quantitative composition

The data and documents to be attached to the marketing authorisation application shall be submitted in accordance with the following provisions.

1. Qualitative composition:

The term "qualitative composition" of the medicinal product shall mean the designation or description of all its components:

the active principle or active principles;

the component or components of the excipient, whatever its nature or the quantity used, including the colouring agents, preservatives, adjuvants, stabilizers, thickeners, emulsifiers, taste correctors, agents aromatics, etc;

the components of the outer coverage of the drugs (capsules, gelatin capsules, etc.) that will be ingested or administered to the animals in another way.

These indications should be supplemented by any useful information on the packaging and, where appropriate, the type of closure, and the devices used for the use or administration of the package must also be described in detail. medication and to be supplied along with it.

2. Designation of the components of the medicinal products:

In the case of products listed in the European Pharmacopoeia or, failing that, in the national pharmacopoeia of one of the Member States, the main name collected in the heading of the corresponding monograph, with reference to the pharmacopoeia concerned.

For the other products, the international common name recommended by the World Health Organization, which may be accompanied by another common name or, failing that, the exact scientific name; products which do not have a common international name or an exact scientific name, shall be designated by reference to their origin and method of production, with any other useful observation being supplemented, if any required.

For colouring matters, the designation by the indicative "E" attributed to them by Council Directive 78 /25/EEC of 12 December 1977 on the approximation of the laws of the Member States relating to: the materials that may be added to the medicinal products for colouring.

3. Quantitative composition:

(a) In order to provide the "quantitative composition" of all the active substances of the medicinal product, it is necessary, in the pharmaceutical form, to specify the mass or number of units of biological activity either per dose or per mass or volume unit of each active substance.

The units of biological activity will be used in substances that cannot be defined in chemical terms.

When the World Health Organization has defined an international unit of biological activity, it is the one that should be used. In cases where an international unit has not been defined, the units of biological activity shall be expressed in such a way as to provide unambiguous information on the activity of the principle.

Where possible, the biological activity shall be indicated per unit of mass or volume.

It will also be expressed, as additional information:

in the case of injectables, the mass or units of biological activity of each active substance contained in the unit container, taking into account, where appropriate, the usable volume of the product after reconstitution;

in the case of medicinal products administered in the form of drops, the mass or units of biological activity of each active substance contained in the number of drops corresponding to 1 ml or 1 g of preparation;

in the case of syrups, emulsions, granules or any other pharmaceutical form which is administered in measured quantities, the mass or units of biological activity of each active substance by measured quantity.

(b) Active substances present in the form of compounds or derivatives shall be designated quantitatively by their total mass and, if necessary or sourced, by the mass of the active fraction or fractions of the molecule.

(c) In the case of medicinal products containing an active substance for the first time in any Member State, an application for a marketing authorisation, the quantitative composition of a medicinal product, shall be used for the first time. an active substance which is a salt or a hydrate shall be systematically expressed in terms of mass of the active fraction or fractions of the molecule. In all cases of medicinal products authorised subsequently in the Member States, the quantitative composition shall be indicated in the same way for the same active substance.

4. Pharmaceutical development:

The choice of composition, components and container, as well as the intended function of the excipients in the finished product, will be explained. This explanation shall be justified by scientific data relating to the development of galenic. Overdosage in the manufacture shall be indicated and justified.

B. Description of the manufacturing method

The description of the manufacturing method to accompany the marketing authorisation application shall be drawn up in such a way as to give a clear picture of the nature of the operations carried out.

For this purpose, this description must include at least:

a reference to the different stages of the manufacturing process, which allows to assess whether the procedures used to produce the pharmaceutical form have been able to cause an alteration of the components;

in case of continuous manufacturing, complete information on the measures taken to ensure the homogeneity of the finished product;

the actual manufacturing formula, with a quantitative indication of all the substances used, however, indicate the quantities of the excipient in an approximate manner, in so far as the pharmaceutical form so requires; make reference to substances which may disappear during the course of the manufacturing process; any overdosage in the manufacture shall be indicated and justified;

the indication of those stages of manufacture in which samples are taken in order to carry out control analysis during the process, when of other data appearing in the documents attached to the application for authorisation is provided that such analyses are necessary for the quality control of the finished product;

experimental validation studies of the manufacturing process where this is unusual or of decisive importance for the product;

in the case of sterile drugs, the details of aseptic procedures and/or the sterilization processes used.

C. Control of the starting materials

1. 'Starting materials' means all components of the medicinal product and, if necessary, of the packaging.

In the case of:

An active substance that is not described in the European Pharmacopoeia or in the pharmacopoeia of any Member State,

An active substance described in the European Pharmacopoeia or in the pharmacopoeia of a Member State, if prepared in accordance with a method which may leave impurities not mentioned in the monograph of the Pharmacopoeia, and whose quality cannot be controlled by this monograph, which has been manufactured by a person other than the applicant, the latter may provide that the manufacturer of the substance shall provide the competent authorities with the description. detailed method of manufacture, of quality control during manufacture and of the validation of the process. In this case, however, the manufacturer must provide the applicant with all the data which may be necessary for the latter to take responsibility for the medicinal product. The manufacturer shall undertake in writing before the applicant to ensure the constancy of the lots and not to modify the manufacturing process or specifications without informing him. The necessary data and documents shall be submitted to the competent authorities in support of such a request for modification.

In the data and documents attached to the application for authorisation, the results of the tests, including the analysis of lots, in particular in the case of active substances, relating to the control of the quality of all the components used. These data and documents shall be submitted in accordance with the following requirements.

1.1 Starting materials registered in pharmacopoeas: The monographs of the European Pharmacopoeia shall be applicable to all the products listed therein.

For other products, each Member State may require the observance of its national pharmacopoeia in relation to the products manufactured in its territory.

The components with respect to the requirements of the European Pharmacopoeia or the pharmacopoeia of one of the Member States. In such cases, the description of the methods of analysis may be replaced by a detailed reference to the pharmacopoeia concerned.

However, when a starting material included in the European Pharmacopoeia or in that of a Member State has been prepared following a method which could leave impurities not controlled in the monograph of the pharmacopoeia of in question, these impurities must be marked, with an indication of their maximum permissible limit, and an appropriate test method must be proposed.

In all cases, the colours must meet the requirements laid down in Directive 78 /25/EEC.

The systematic tests carried out on each batch of starting materials shall be carried out as described in the application for marketing authorisation. If tests other than those mentioned in the pharmacopoeia are used, it must be proved that the starting materials meet the quality requirements of that pharmacopoeia.

In cases where the specification of a monograph of the European Pharmacopoeia or the national pharmacopoeia of a Member State is not sufficient to ensure the quality of the product, the competent authorities may require specifications more appropriate to the marketing authorisation holder.

The competent authorities shall inform the authorities responsible for the pharmacopoeia concerned thereof.

The holder of the product marketing authorisation shall communicate to the authorities responsible for that pharmacopoeia the details of the alleged insufficiency and the additional specifications that have been provided.

Where a starting material is not described in the European Pharmacopoeia or in the pharmacopoeia of a Member State, it is permissible for the pharmacopoeia of a third country to be followed; in such cases, the applicant shall present a copy of the monograph accompanied, where necessary, by the validation of the analytical procedures contained in the monograph and, where appropriate, a translation.

1.2 Starting materials not included in a pharmacopoeia: Components not listed in any pharmacopoeia shall be the subject of a monograph referring to each of the following points:

the name of the substance, which shall comply with the requirements of Section A (2), shall be supplemented by commercial or scientific synonyms;

the definition of the substance, which is similar to that used in the European Pharmacopoeia, shall be accompanied by all the necessary explanations, in particular as regards the molecular structure, if applicable; an appropriate description of the synthesis method must be attached. Where products cannot be defined more than by their method of manufacture, the method must be sufficiently detailed to characterise a constant product as to its composition and its effects;

the means of identification, which may be described in the form of the complete techniques followed for obtaining the product, and in the form of the tests to be carried out systematically;

purity checks shall be described according to the set of foreseeable impurities, in particular those which may produce harmful effects and, if necessary, those which, taking into account the association of substances which are the subject of the application, may have a negative impact on the stability of the medicinal product or disturb the analytical results;

as regards complex products of plant or animal origin, the case in which the multiplicity of pharmacological actions requires chemical, physical or biological control of the main components and that of the another case of products containing one or more groups of similar principles of activity for which a global method of dosing can be accepted;

when using materials of animal origin, the measures necessary to ensure the absence of potentially pathogenic agents shall be described;

any special precautions to be taken for the preservation of the starting material and, if necessary, the maximum storage period before a new analysis.

1.3 Physical-chemical characteristics that may change the bioavailability: The following data, concerning the active substances entered or not in the pharmacopoeias, should be provided as elements of the the general description of the active substances, when they condition the bioavailability of the medicinal product:

crystalline form and solubility coefficients,

dimension of the particles, if any after spraying,

solvation status,

oil/water distribution coefficient.

The first three paragraphs will not apply to substances that are used only in solution.

2. Where basic materials such as micro-organisms, tissues of plant or animal origin, cells or fluids (including blood) of human or animal origin as well as cellular constructions are used in the manufacture of the veterinary medicinal product The origin and history of the starting materials shall be described and documented.

The description of the starting material shall comprise the production strategy, the purification or inactivation procedures, together with its validation, and all control procedures during the process for which the purpose is ensure the quality, safety and constancy of the batches of the finished product.

2.1 When cell banks are used, it must be demonstrated that the characteristics of the cells have remained unchanged in the steps used for production and subsequently.

The competent authorities may also request pK and pH values if they consider this information to be indispensable.

2.2 The inoculum materials, the cell banks, the serum and other materials of biological origin, as well as, wherever possible, the starting materials from which they have been obtained must be tested for testing which are free from adventitious agents.

When the presence of potentially pathogenic adventitious agents is unavoidable, only the material will be used if the subsequent treatment ensures the elimination or inactivation of such agents, which must be validate.

D. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies

The applicant must demonstrate that the veterinary medicinal product has been manufactured in accordance with the explanatory note on how to minimise the risks of transmission of animal spongiform encephalopathy agents through the veterinary medicinal products and their updates, published by the European Commission in Volume 7 of its publication Rules on veterinary medicinal products in the European Community.

E. Control tests performed at an intermediate stage of the manufacturing process

The data and documents attached to the marketing authorisation application shall include those relating to the checks which may have been carried out on products which are at an intermediate stage. of the manufacturing process in order to ensure the constancy of the technological characteristics and the manufacturing process.

Such tests shall be essential to check the suitability of the medicinal product to the formula in the exceptional cases where the applicant proposes, in order to test the finished product, an analytical method which does not include the the determination of all the active substances (or those components of the excipient subject to the same requirements as the active substances).

The above will also apply when the quality control of the finished product depends on the tests carried out during the process, especially in the case that the product is mainly defined by its method of manufacturing.

F. Testing of the finished product

1. For the purposes of the control of the finished product, the batch of a finished product shall mean the assembly of units of a pharmaceutical form which come from the same initial quantity of material and have undergone the same series of operations as manufacture and sterilisation or, in the case of a continuous production process, the set of units manufactured within a given time span.

The marketing authorisation application shall contain a list of the tests which are carried out in a systematic manner with each batch of finished products. The frequency of tests which are not carried out in a systematic manner shall be recorded. The approval limits will be indicated.

Among the data and documents attached to the marketing authorisation application, those referring to the checks carried out on the finished product at the time of approval shall be included. Such checks shall be submitted in accordance with the following requirements.

The provisions of the general monographs of the European Pharmacopoeia or, failing that, the pharmacopoeia of a Member State shall apply to all products defined therein.

If test methods and limits other than those mentioned in the monographs of the European Pharmacopoeia or, failing that, of the national pharmacopoeia of a Member State are used, it shall be demonstrated that, in the case of a test in accordance with these monographs, the finished product would meet the qualitative requirements of the pharmacopoeia applicable to the pharmaceutical form in question.

1.1 General characteristics of the finished product: The tests of a product will always include certain controls of the general characteristics of the product. Such checks shall, in so far as it is appropriate, refer to the determination of the average masses and the maximum deviations, mechanical, physical or microbiological tests, the organoleptic characteristics, the physical characteristics such as the density, pH, refractive index, etc. The applicant shall define, in each particular case, the rules and the tolerance limits for each of these characters.

The conditions of the tests and, where appropriate, the apparatus or equipment used and the standards shall be accurately described when they are not included in the European Pharmacopoeia or in the national pharmacopoeia of the Member States or where they are not the methods prescribed by those pharmacopoeas.

In addition, the solid pharmaceutical forms to be administered orally shall be subjected to in vitro studies of the release and the speed of dissolution of the active substance or principle. in the case of another type of administration if the competent authorities of the Member State concerned consider it necessary.

1.2 Identification and determination of the active substance or principles: The identification and determination of the active substance or principles shall be carried out either on a representative sample of the manufacturing batch or on a a number of doses analysed in isolation.

Unless justified, the maximum tolerable deviation of the content of the active substance in the finished product shall not exceed ± 5% at the time of manufacture.

On the basis of stability tests, the manufacturer shall propose and justify acceptable maximum tolerance limits for the content of the active substance in the finished product applicable throughout the period of validity. proposed for the product.

In certain exceptional cases of particularly complex mixtures, in which the determination of the active principles, very numerous or present only in very small proportions, requires equally complex investigations and The determination of one or more active substances in the finished product may be omitted with the express condition that these determinations are carried out at intermediate stages of the manufacturing process, and that the determination of one or more active substances in the finished product may be omitted. manufacture. This derogation shall not extend to the characterisation of such substances. This simplified technique shall be supplemented by a quantitative assessment method which enables the competent authorities to adapt the medicinal product to the specifications after they are placed on the market.

If the physico-chemical methods are not sufficient to provide sufficient information on the quality of the product, a biological test will be required in vitro or in vivo. Where possible, reference materials and statistical analysis should be used in this test to allow the calculation of the confidence limits.

When these tests cannot be carried out with the finished product, it will be permissible to be carried out in an intermediate stage, as close as possible to the end of the manufacturing process.

When of the data supplied in accordance with the provisions of Section B, it is apparent that in the manufacture of the medicinal product an important overdose of an active substance is used, the description of the methods of control The finished product shall include, where appropriate, the chemical study and, if necessary, the toxicopharmaceutical study of the alteration suffered by this substance, with characterization or determination, if applicable, of the degradation products.

1.3 Identification and determination of the components of the excipient: To the extent necessary, the components of the excipient or excipients shall be at least the object of identification tests.

The technique presented for the identification of the colorants shall allow the verification of the following in the annex to Directive 78 /25/EEC.

An upper and lower limit test shall be obligatory for the preservative agents and for a higher limit test any other constituent of the excipient which may adversely affect the functions The excipient shall be subject to a higher and lower limit test if it can act on the bioavailability of an active substance unless the bioavailability is guaranteed by other appropriate tests.

1.3 Safety tests: Irrespective of the toxicopharmaceutical tests submitted with the application for marketing authorisation, the details of the safety tests shall be included in the analytical dossier. as, for example, sterility, bacterial endotoxins, pyrogens and local tolerance in animals, in all cases where such tests should be carried out systematically to check the quality of the product.

G. Stability tests

The data and documents to be attached to the marketing authorisation application shall be submitted in accordance with the following indications:

The investigations that have allowed the determination of the validity period, the recommended conditions for conservation and the specifications at the end of the period of validity proposed by the applicant should be described.

In the case of premixtures for medicated feedingstuffs, the necessary information on the period of validity of medicated feedingstuffs manufactured with such premixtures shall also be included, in accordance with the instructions of the recommended usage.

If a finished product has to be reconstituted prior to administration, details of the proposed shelf-life for the reconstituted product shall be specified, together with relevant data on the product concerned. stability.

In the case of multidose vials, stability data shall be submitted to justify the period of validity of the vial after first use.

When a finished product can result in degradation products, the applicant shall indicate them, indicating the methods of characterization and the analytical procedures.

The conclusions should include the results of the analyses, justifying the proposed shelf-life in the recommended storage conditions, as well as the specifications of the finished product at the end of the test. period of validity in such recommended storage conditions.

The maximum acceptable level of degradation products shall be indicated at the end of the validity period.

A study will be presented on the interaction of the product and the container in cases where such interaction is possible, especially in the case of injectable preparations or aerosols for internal use.

PART 3

Safety and study of waste tests

The data and documents to be attached to the marketing authorisation application shall be submitted in accordance with the following indications.

Member States shall ensure that the tests are carried out in accordance with the principles of good laboratory practice

A. Safety tests

Conducting the tests:

1. Introduction: The documentation on safety must show:

(a) the potential toxicity of the medicinal product and the dangerous or negative effects which may occur in the animal under the proposed conditions of use; these effects shall be assessed in the light of the seriousness of the pathological process of in question;

(b) the possible harmful effects on man of the residues of the veterinary medicinal product or substance present in foodstuffs from treated animals and the inconveniences which may be created by such residues in the industrial processing of foodstuffs;

(c) the potential risks that may result from the exposure of the man to the medicinal product, for example during the administration of the medicinal product to the animal;

4) possible risks to the environment due to the use of the medicinal product. All results must be reliable and of general application. To the extent that it is appropriate, mathematical and statistical procedures will be used for the elaboration of the experimental methods and the assessment of the results. In addition, it will be necessary to inform clinicians about the therapeutic potential of the product and the risks attached to its use.

In some cases it may be necessary to test the metabolites of the original compound when they constitute the waste in question.

An excipient that is used for the first time in the pharmaceutical field should be considered as an active substance.

2. Pharmacology: The pharmacological studies are fundamental to the evidence of the mechanisms of production of the therapeutic effects of the drug. Therefore, the pharmacological studies carried out on species of target animals and experiments shall be included in Part 4.

However, pharmacological studies may also be useful for the analysis of toxicological phenomena. In addition, if a medicinal product causes a pharmacological effect free of toxicity or the effect is achieved with doses lower than the needs to produce toxicity, this pharmacological effect should be taken into account when assessing safety. of the product.

Therefore, the details of the pharmacological studies carried out on laboratory animals, as well as the relevant information concerning the clinical studies carried out with the target animal should always precede the documentation on the safety.

3. Toxicity:

3.1 Single Dose Toxicity: Single-dose toxicity study may be useful for predicting:

possible effects on the target animal species following acute overdose,

possible effects after accidental administration in man,

the appropriate doses for the study of repeated administration.

The single dose toxicity study should highlight the acute toxic effects of the substance and the time it takes for them to appear and refer.

In principle, the study should be conducted with at least two mammalian species. One of these species may be replaced, where appropriate, by an animal species to which the medicinal product is intended. At least two routes of administration should normally be used; one of them will be identical, or similar, to the proposal for the target species. If a considerable exposure of the user to the medicinal product is anticipated, e.g. by inhalation or dermal contact, these pathways will need to be studied.

In order to reduce the number of animals used and their suffering, new protocols are being continuously put in place to carry out the single dose toxicity test. Studies conducted in accordance with these new procedures shall be accepted if they are properly validated, as well as those in accordance with internationally recognised and established guidelines.

3.2 Toxicity by continued administration: Continuous administration toxicity tests will be intended to reveal the physiological or pathological changes that follow the repeated administration of the principle. active or association of active substances being studied, and establish the relationship of these alterations to the posology.

In the case of substances or medicinal products intended to be administered only to non-food-producing animals, the study of toxicity by continuous administration in a species of animal species shall be sufficient in principle. experimentation. This study may be replaced by a study carried out on the target animal. The frequency and route of administration, as well as the duration of the study, shall be determined taking into account the intended clinical conditions. The investigator shall justify the extent and duration of the tests, as well as the doses chosen.

In the case of substances or medicinal products to be administered to food-producing animals, the study shall be carried out at least in two species, one of which shall not belong to the order of the rodents. The researcher shall justify the choice of species, based on the knowledge acquired on the metabolism of the product in animals and man. The test substance shall be administered orally. The duration of the test shall be at least 90 days. The investigator shall clearly describe and justify the method and frequency of the administration, as well as the duration of the tests.

In principle, the maximum dose should be chosen in such a way as to make the harmful effects appear. The minimum dose should not cause any toxic effects. The evaluation of the toxic effects will be based on the observation of the behavior and growth, on the hematological and physiological analyses particularly of the excrement organs, and also on the necropsique reports accompanied by the tests. histological. The choice and extent of each test group will depend on the animal species being used and the state of scientific knowledge.

In the case of new associations of known substances which have been studied in accordance with the provisions of this royal decree, the investigator may, if justified, modify the evidence of continuous administration, except where toxicity tests have revealed potentiation or new toxic effects.

3.3 Tolerance in the target animal: Any sign of intolerance observed during the study carried out with the target species in accordance with the requirements of Section B of Chapter I of the Annex shall be described in detail. Part 4. The study, the species and the breed in question shall be indicated, as well as the dose to which intolerance is expressed. Any unforeseen physiological changes shall also be included.

3.4 Toxic effects on reproductive function, including teratogenicity:

3.4.1 Study of effects on reproduction: The purpose of the study is to detect possible changes in reproductive function in the male or female, or the existence of harmful effects for prole after administration. of the medicinal product or substance under investigation.

In the case of substances or medicinal products to be administered to food-producing animals, the study of effects on the reproductive function should cover at least two generations in a species, usually a rodent. The substance or product under study shall be administered to males and females at an appropriate time prior to mating. This administration will be extended to the weaning of the second generation subsidiary. At least three different doses shall be used. The maximum dose shall be selected in such a way as to make the harmful effects appear. The minimum dose should not cause any toxic effects.

The assessment of effects on reproductive function will be based on fertility, pregnancy and maternal behavior, breastfeeding, growth and development of the first generation from conception to life. maturity, and in the development of the second-generation subsidiary to the weaning.

3.4.2 Study of embryo and foetal toxicity, including teratogenicity: In the case of substances or medicinal products to be administered to animals intended for food production, toxicity shall be considered. embryonic and fetal, including teratogenecity. This study will be conducted at least in two species of mammals, usually a rodent and rabbit. The test protocol (number of animals, dose, time of administration and evaluation criteria of the results) will depend on the state of scientific knowledge at the time the application is submitted and the level of statistical significance to be achieved. The rodent study may be combined with the study of effects on reproductive function.

In the case of substances or medicinal products which are not intended for use in animals intended for food production, embryo and foetal toxicity, including teratogenicity, at least one species shall be studied, which may be the target species, if the product is intended for animals which may be used for breeding.

3.5 Mutagenicity: The mutagenicity test is intended to determine the ability of a substance to cause transmissible changes in cell genetic material.

The mutagenic properties of any new substance to be used in veterinary medicinal products shall be assessed.

The number and types of tests, as well as the criteria for evaluating the results, will depend on the state of scientific knowledge at the time the application is submitted.

3.6 Carcinogenicity: Long-term carcinogenicity studies in animals will be necessary in the case of a substance with which man can come into contact:

this presents a close chemical analogy with known carcinogenic substances,

if, during the mutagenicity test, the substance has produced any manifestation indicating a possible carcinogenicity,

if, during the toxicity test, the substance has caused suspicious signs.

The state of scientific knowledge should be taken into account at the time the application is submitted to design the carcinogenicity study and assess its results.

3.7. Exceptions: The systemic absorption of medicinal products for topical use in the target animal species should be studied. If this absorption is shown to be negligible, the toxicity tests for continued administration, the study of toxic effects in the reproductive function and the carcinogenicity study may be omitted unless:

be expected to be swallowed by the animal under the established conditions of use,

the medicine may come into contact with food products from the treated animal (intramammary preparations).

4. Other requirements:

4.1 Immunotoxicity: When studies with continuous administration performed in animals, specific alterations in the weight or histology of the lymphoid organs and changes in the cellularity of the lymphoid tissue are observed. the bone marrow or circulating lymphocytes, the investigator shall consider the need for further examination of the effects of the medicinal product on the immune system.

The state of scientific knowledge shall be taken into account at the time the application is submitted to design such examinations and assess the results.

4.2. Microbiological properties of waste:

4.2.1. Potential effects on the human gut flora.

The microbiological risk posed by residues of antimicrobials for human gut flora will be investigated, and this is in accordance with the state of scientific knowledge at the time of the present request.

4.2.2 Potential effects on micro-organisms used in the industrial transformation of food products

In some cases it may be necessary to carry out tests to determine whether the waste can hinder the technical processes of industrial processing of food products.

4.3 Observations on the therapeutic use in humans: Information will be provided to demonstrate whether the components of the veterinary medicinal product have a therapeutic use in humans or not. If yes, a report should be drawn up on all the effects observed in humans (including adverse reactions) and their causes, to the extent that they may be important in assessing the medicinal product. The results of the tests presented in the literature shall be supported, where appropriate, in support of the results of the tests. If the constituents of the veterinary medicinal product do not have or no longer have a therapeutic use in humans, the reasons shall be given.

5. Ecotoxicity:

5.1 The purpose of the study of the ecotoxicity of a veterinary medicinal product is to assess the harmful effects on the environment which may result from the use of the product and to define the measures which may be necessary to reduce the risk.

5.2 The assessment of ecotoxicity shall be mandatory in any application for the marketing authorisation of a veterinary medicinal product other than applications.

5.3 Generally, the evaluation will take place in two phases.

In the first phase, the investigator should assess the potential for the product, the active substances or the metabolites to come into contact with the environment. You will consider this:

the target species and the proposed pattern of use (e.g., collective or individual medication),

the mode of administration and, in particular, the likely degree of direct incorporation of the product into the ecosystem,

the possibility that the product, the active substances or their metabolites pass from the animals treated to the environment by excretion, and the persistence of the excreta,

disposal of waste or product that has not been used.

In the second phase, the researcher will assess the need to further study the effects of the product on certain ecosystems, taking into account the degree of exposure of the product to the environment and the information on the physico-chemical, pharmacological and/or toxicological properties of the compound, obtained by the other tests and tests established by this royal decree.

5.4 Where appropriate, additional research will be required on:

the target and the behavior on the ground,

the destination and behavior in the water and in the air,

the effects on aquatic organisms,

effects on organisms other than the target organism.

These additional studies should be carried out in accordance with the test of protocols set out in Annex V to Council Directive 67 /548/EEC of 27 June 1967 on the approximation of provisions laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances or, where a particular point is not adequately covered by these protocols, in agreement with other internationally recognised on the veterinary medicinal product, the active substances or the metabolites excreted, as appropriate. The number and type of evidence, as well as the assessment criteria, shall depend on the state of scientific knowledge at the time the application is made.

6. Presentation of data and documents:

As in all scientific work, the dossier of safety tests must include:

a) an introduction in which the object is defined, along with the appropriate bibliographic data;

(b) the detailed identification of the substance under study, including the following data:

international common name (DCI),

name of the International Union of Pure and Applied Chemistry (UIQPA),

CAS number (Chemical Abstract Service),

therapeutic and pharmacological classification,

synonyms and abbreviations,

structural formula,

molecular formula,

molecular weight,

degree of impurities,

qualitative and quantitative composition of impurities,

description of the physical properties,

merge point,

boiling point,

steam pressure,

solubility in water and in organic solvents expressed in g/l, with an indication of the temperature,

density,

refraction spectrum, rotation, etc;

(c) a detailed experimental plan justifying the possible absence of certain tests referred to above, a description of the methods followed, the apparatus and materials used, the species, breed or lineage of the animals, from their origin, and, each time they are available, their number and the conditions of accommodation and feeding, specifying, inter alia, whether they are free from specific pathogens (SPF);

d) all results obtained, whether favorable or unfavorable. The original data must be sufficiently detailed to allow for a critical assessment, regardless of the author's interpretation. Illustrations can be added to the results, as an explanation;

e) a statistical analysis of the results, when required by the scheduling of the tests, and the discrepancy between the data;

f) an objective discussion of the results achieved that provides conclusions on the safety of the substance, on the safety margins in the experimental animal and on the target animal and the possible reactions adverse effects, on the field of application, on effective doses and possible incompatibilities;

g) a detailed description and a thorough discussion of the results of the study of the safety of residues in foodstuffs and their importance in the assessment of the potential risks involved waste for man. A series of proposals will be attached to the discussion to ensure that the application of internationally recognised criteria excludes any danger to man, for example, doses of zero effect on animals, proposals for the election of the safety factor and acceptable daily intake (ADI);

h) a detailed discussion of all risks for people who prepare the drug or administer it to animals, accompanied by appropriate measures to reduce such risks;

i) a detailed discussion of possible environmental risks due to the use of the veterinary medicinal product under the proposed practical conditions, accompanied by appropriate suggestions for reducing such risks;

(j) all information necessary to ensure that the clinician knows to the greatest extent possible the usefulness of the product concerned. The indications referring to the adverse reactions and the possible treatment of acute toxic reactions in the animal to which the medicinal product is to be administered shall be added;

(k) a report by the expert containing a detailed critical analysis of the above information, carried out in accordance with the state of scientific knowledge at the time the application is made, together with a detailed summary of all relevant safety test results and accurate bibliographic references.

B. Study of waste

Conducting the tests:

1. Introduction:

For the purposes of this royal decree, "residues" shall mean all the active substances or their metabolites which remain in the meat or other foodstuffs from the animal to which the medicinal product has been administered. in question.

The purpose of the study of waste is to determine whether residues persist in foodstuffs from treated animals, and, if so, under what conditions and to what extent, and the periods of elimination. which must be respected in order to exclude any risk to human health as well as the disadvantages for the industrial processing of foodstuffs.

The risk assessment due to the residues shall include tests to determine whether they are found in the animals treated under the recommended conditions of use, as well as the study of their effects.

In the case of veterinary medicinal products for food-producing animals, the documentation relating to the waste must show:

(a) to what extent and how long the residues of the veterinary medicinal product or its metabolites persist in the tissues of the treated animal or the food products thereof;

(b) it is possible to establish, in order to prevent any risk to the health of the consumer of foodstuffs from treated animals or the disadvantages in the industrial transformation of those, a period (a) a reasonable suppression that can be observed in the practical farming conditions;

(c) there are routine practical analytical methods to ensure that compliance with the deletion period is systematically checked.

2. Metabolism and Kinetics of Waste:

2.1 Pharmacokinetics (absorption, distribution, biotransformation and elimination): The pharmacokinetic study of residues of veterinary medicinal products is intended to evaluate absorption, distribution, biotransformation and disposal of the product in the target species.

The maximum recommended dose of the finished product or a bioequivalent formulation shall be administered to the target species.

The extent of absorption of the medicinal product will be described in detail depending on the mode of administration used.

If the systemic absorption of a topical product is shown to be negligible, further study is not necessary.

The distribution of the medicinal product in the target animal will be described; consideration will be given to the possibility of the product being fixed to plasma proteins or to milk or eggs, as well as the accumulation of lipophilic compounds.

The elimination pathways of the product in the target animal will be described and the major metabolites will be identified and characterized

2.2 Waste depletion: This study, which consists of measuring the rate of waste depletion in the target animal after the last administration of the medicinal product, is intended to allow for the determination of the period deletion.

The amount of residues present in the experimental animal shall be determined at different times after the last administration of the medicinal product, using appropriate physical, chemical or biological methods; indicate the technical procedure as well as the reliability and sensitivity of the method used.

3. Method of systematic analysis of waste detection:

The proposed method of analysis should be able to be carried out during systematic checks and have a degree of sensitivity to identify with certainty the presence of residues in quantities higher than the legal limits. allowed.

This method must be validated and simple enough to be applied in the normal conditions of systematic waste control.

A detailed description of the method, which must include the following data:

specificity,

accuracy, including sensitivity,

precision,

limit of detection,

limit of quantification,

practicability and applicability under normal laboratory conditions,

susceptibility to interference.

The suitability of the proposed analytical method shall be assessed in the light of the state of scientific knowledge at the time the application is made.

Presentation of the data and documents: As in all scientific work, the dossier of the study of the waste must include:

a) an introduction in which the object is defined, along with the appropriate bibliographic data;

(b) the detailed identification of the medicinal product, including the following data:

1. composition,

2. purity,

3. Batch identification,

4. relationship to the finished product,

5. specific activity and radiological purity of the substances marked,

6. position of the atoms marked on the molecule;

(c) a detailed experimental plan justifying the possible absence of certain tests mentioned above, a description of the methods followed, the equipment and materials used, the species, breed or lineage of the the animals, their origin, their number and the conditions of accommodation and food;

d) all results obtained, whether favorable or unfavorable. The original data must be sufficiently detailed to allow for a critical assessment, regardless of the author's interpretation. Illustrations can be added to the results;

e) a statistical analysis of the results, when required by the scheduling of the tests, and the discrepancy between the data;

f) an objective discussion of the results achieved. The proposed maximum limits for the residue of active substances contained in the product shall be included, specifying the marker residue and the target tissues. A period of abolition shall also be proposed to ensure the absence of potentially harmful residues for consumers in foodstuffs from treated animals;

g) a final expert report containing a detailed critical analysis of the above information, carried out in accordance with the state of scientific knowledge at the time the application is made, together with a detailed summary of all the results of the study of the waste and precise bibliographic references.

PART 4

Preclinical and clinical studies: The data and documents that are attached to the marketing authorization application, as provided for in this royal decree

Preclinical requirements: Preclinical studies are intended to determine pharmacological activity and product tolerance.

A. Pharmacology

A. 1 Pharmacodynamics: The pharmacodynamic study should be carried out following two different approaches.

On the one hand, the mechanism of action and the pharmacological effects on which the recommended practical application is based will be adequately described, expressing the results quantitatively (dose-effect curves, time-effect or other) and, as far as possible, comparing them with those of a product whose activity is known. When it is said of an active substance that has superior efficacy, the difference must be demonstrated and it is statistically significant.

Furthermore, the investigator will provide a comprehensive pharmacological assessment of the active substance, with particular reference to the possibility of adverse reactions. The main functions should generally be examined.

The investigator will study the effects of the route of administration, formulation, etc., on the pharmacological activity of the active substance.

Further research will be done when the recommended dose is close to the dose that causes adverse reactions.

When experimental techniques are not commonly used, they shall be described in such a way as to permit their reproduction, and the investigator shall demonstrate their validity. The results of the tests shall be clearly expressed and, in the case of a particular type of test, reference shall be made to their statistical significance.

It shall also be investigated, unless appropriate justification, any quantitative modification of the effects resulting from repeated administration of the product.

Drug associations may be well justified by pharmacological needs, or by clinical indications.

In the first case, the pharmacodynamic or pharmacokinetic study should highlight those interactions that make the association recommended for clinical use. In the second case, where clinical experimentation is intended to scientifically justify the association of medicinal products, the investigator shall verify that the expected effects of the association can be demonstrated in animals and shall, as the importance of adverse reactions. If an association includes a new active substance, the latter should be the subject of a thorough prior study.

A. 2 Pharmacokinetics: Generally, the basic pharmacokinetic data of a new active substance have clinical utility.

Pharmacokinetics have two main areas:

1) the descriptive pharmacokinetics that allows to determine the basic parameters such as body clearance, volume or volumes of distribution, average length of stay, etc.;

2) the use of these parameters in the study of the relationship between posology, plasma and tissue concentration and pharmacological, therapeutic or toxic effects.

In general, the pharmacokinetic study in the target species is necessary to use medicinal products with the highest possible efficacy and safety. This study is of particular relevance to the clinician in determining the dosage (route and place of administration, dose, range between doses, number of administrations, etc.) and to establish this according to certain variables of the population (age, disease, etc.). In some animals, this study may be more effective and generally provides more information than classic dose assessment studies.

When it comes to new associations of known substances that have been studied according to the provisions of this royal decree, the pharmacokinetic study of the fixed association will not be necessary if it can be shown that the administration of the active substances in an associated manner does not change their pharmacokinetic properties.

A. 2.1 Bioavailability/Bioequivalence: Relevant studies on bioavailability to determine bioequivalence will be performed in the following cases:

to compare the new formulation of a drug with the existing one,

to compare a new mode or administration path with one already set,

B. Tolerance in the target animal species

The study will be carried out on all animal species to which the medicinal product is intended. The local and general tolerance tests shall be carried out on all these animal species in order to determine a tolerated dose allowing adequate safety margins, as well as clinical symptoms of intolerance, using the pathway or pathways. recommended, in so far as this can be achieved by increasing the therapeutic dose or duration of treatment. The foreseeable pharmacological effects and adverse side effects shall be described in the test report as possible. The evaluation of these will be done taking into account that the animals used can be very valuable.

The medicine will be administered at least by the recommended route.

C. Resistance

In the case of medicinal products used in the prevention or treatment of infectious diseases or parasitic infestations in animals, the occurrence of resistant organisms shall be reported.

Clinical requirements:

1. General principles: The purpose of clinical trials is to show or test the effect of the veterinary medicinal product after administration of the recommended dose and to establish the indications and contraindications for the species, age, race and sex, instructions for use and any possible side effects, as well as safety and tolerance under normal conditions of use.

Unless justified, clinical trials shall be conducted with control animals (controlled clinical trials). The effect obtained will be compared to the effect of a placebo, with the absence of treatment or the effect of an authorised medicinal product consisting of the therapeutic value. All results obtained, whether positive or negative, shall be reported.

The methods used for diagnosis will be explained and the results will be classified according to conventional or quantitative clinical criteria. Appropriate statistical methods shall be used which shall be justified.

In the case of a veterinary medicinal product used primarily as a production stimulant, particular attention shall be paid to:

to the performance of the animal product, to the quality of the animal (organoleptic, nutritional, hygienic and technological qualities),

to the nutritional effectiveness and growth of the animal,

to the general health status of the animal.

The experimental data must be confirmed with the data obtained under practical field conditions.

When the applicant can prove that it is not in a position to provide comprehensive information on the therapeutic effect in relation to certain therapeutic indications:

either because the medicinal product in question is indicated in such rare cases that the applicant is reasonably not expected to expect comprehensive data, either because comprehensive information cannot be provided in the state of the scientific knowledge of the moment.

The granting of the marketing authorisation may be subject only to compliance with the following conditions:

the medicinal product concerned shall be supplied only by veterinary prescription and, in certain cases, administered exclusively under strict veterinary control,

the package leaflet and any other information should indicate to the veterinarian that the information available on the medicinal product in certain respects. which shall be specified. is, for the time being, incomplete.

2. Performance of the tests: All veterinary clinical trials shall be carried out in accordance with a detailed test protocol to be recorded in writing before the start of the test. During the preparation of any test protocol and throughout the test protocol, the welfare of the test animals, which shall be the subject of veterinary supervision, shall be taken into account at all times.

Preestablished written procedures concerning the organisation, performance, data collection, documentation and testing of clinical trials shall be systematically required.

Before starting any test, it will be necessary to obtain and document the consent with knowledge of the cause of the owner of the animals to be used in the test. In particular, the owner of the animals shall be informed in writing of the consequences of the participation in the test with regard to the subsequent destination of the treated animals or the production of foodstuffs from the same. A copy of that notification, dated and endorsed by the owner of the animal, shall be included in the test documentation.

Unless the test is carried out according to a blind method, the provisions concerning the labelling of veterinary medicinal products shall apply by analogy to the labelling of the formulations to be used in the tests. Veterinary surgeons. In all cases, the labelling shall be clearly and indelibly marked as "exclusive use in veterinary clinical trials".

Data and documents:

As in any scientific work, the efficacy dossier should include an introduction in which the object is defined, along with the appropriate bibliographic documentation.

All preclinical and clinical data should be sufficiently detailed to allow for an objective analysis. All studies and trials shall be included, whether favourable or unfavourable to the applicant.

1. Relationship of preclinical observations: Where possible, data will be provided on the results of:

(a) the evidence to show the pharmacological actions;

(b) evidence showing the pharmacological mechanisms responsible for the therapeutic effect;

c) evidence to demonstrate the main pharmacokinetic processes.

If during testing, unexpected results appear, it will be necessary to describe them.

In addition, the following documents will be included in all preclinical studies:

a) a summary;

(b) a detailed experimental plan with the description of the methods, apparatus and material used, the identification of the animals, their species, their age, weight, gender, number and race or lineage, the dosage, route and pattern of administration;

c) an objective discussion of the results obtained, where appropriate;

d) an objective discussion of the results obtained that provides conclusions on the safety and efficacy of the product.

The total or partial default of this data should be explained.

2. Relationship of clinical observations: All researchers should provide the information in individual tokens when the treatment is individual and in collective tokens when the treatment is collective.

The data will be provided as follows:

a) name, address, function and qualification of the responsible investigator;

(b) the place and date of the treatment; name and address of the owner of the animals;

(c) details of the test protocol including a description of the method used, with the aspects to ensure the random and blind character, route and pattern of administration, dosing, identification of animals for experimentation, species, race or lineage, age, weight, sex and physiological status;

(d) method of rearing and feeding, with indication of the composition of the food and the nature and quantity of all additives containing the food;

e) medical history (with all possible information), occurrence and evolution of intercurrent diseases;

f) diagnostic and methods used;

g) symptoms and severity of the disease, according to conventional criteria, if possible;

h) Detailed identification of the formulation used in the clinical trial;

i) dosing of the medicinal product, method and route of administration, dosage and, where appropriate, precautions taken during administration (duration of injection, etc.);

j) duration of treatment and post-observation period;

k) all data on medicinal products which have been administered during the observation period (in addition to the medicinal product under study) either previously or at the same time as the product under study, in which case they will be detailed the interactions observed;

l) all clinical trial results (including unfavorable or negative results) along with an exposure of clinical observations and the results of objective testing of activity (analysis of laboratory, functional tests) necessary to evaluate the application; the techniques used will be described and the variations of the results will be explained (e.g., methodological variants, individual differences or influence of the (a) the testing of the pharmacodynamic effect in the animal shall not be sufficient; to justify conclusion on the therapeutic effect;

m) all information relating to any inadvertent or unintended effects, as well as any subsequent measures that have been taken; as far as possible, the cause-effect relationship shall be investigated;

n) effects on the production of animals (e.g. egg laying, milk production and reproductive function);

or) the impact on the quality of food products from treated animals, in particular when it comes to medicinal products used to stimulate production;

p) a conclusion on each individual case, or collective when the treatment has been.

Any omission of data referred to in points (a) to (p) shall be duly justified.

The marketing authorisation holder of the veterinary medicinal product shall ensure that the original documentation, which forms the basis of the information provided, is kept for at least five years from the moment. when the authorization is withdrawn

3. Summary and conclusions of the clinical observations: A summary of the tests and the results of each clinical trial shall be performed, including:

(a) the number of witnesses, the number of animals treated, individually or collectively, and a breakdown by species, race or lineage, age and sex;

(b) the number of animals whose study has been interrupted before the end, and the reasons for such interruption;

(c) for the control animals, the following information:

if they have not been treated,

if you have received a placebo,

if you have received another known effect medicine,

if they have received the active substance object of study according to another formulation or by another route;

d) the frequency of adverse reactions observed;

(e) comments on the impact on production (e.g. laying of eggs, milk production, reproductive function and quality of the food product);

(f) data on test animals showing particular susceptibility to their age, mode of rearing, feeding or destination, or whose physiological or pathological condition requires special attention;

g) a statistical analysis of the results, when required by the programming of the tests.

Finally, the investigator will draw general conclusions based on the experimental results, and will decide on the safety of the drug under the proposed conditions of use, the therapeutic effect and all information relevant to the indications and contraindications, the dosage and the average duration of the treatment and, where appropriate, the interactions observed with other medicinal products or food additives, as well as the particular precautions to be taken be taken during treatment and clinical symptoms of overdose.

In the case of fixed associations of medicinal products, the investigator should also draw conclusions regarding the safety and efficacy of the product as compared to the administration of the different active substances. separated.

4. Expert report: The final expert report shall include a detailed critical analysis of all pre-clinical and clinical data in the light of the state of scientific knowledge at the time the application is made, together with a summary detailed results of the tests and trials presented and precise bibliographic references.

TITLE II

Requirements for immunological veterinary medicinal products

PART 1

Case Summary

Without prejudice to the special requirements laid down by Community legislation for the control and eradication of animal disease, the following requirements shall apply to veterinary products. immunological.

A. Administrative data

The immunological veterinary medicinal product which is the subject of the application must be identified by name and the name of the active substances, together with the indication, pharmaceutical form, method and route of administration and description of the final sales presentation of the product.

The name and address of the applicant shall be entered, together with the name and address of the manufacturer and sites involved in the different stages of production (including the manufacturer of the finished product and the manufacturer). manufacturer or manufacturers of the principle or the active principles), as well as, where appropriate, the name and address of the importer.

The applicant shall communicate the number and title of the volumes of documentation it sends in support of the application and shall indicate, where appropriate, the samples it attaches.

A document certifying that the manufacturer is authorised to manufacture immunological veterinary medicinal products shall be attached to the administrative data.

On the other hand, the relationship of managed organisms in the production facilities will be included.

The applicant shall present the relationship of the countries in which the authorisation has been granted, copies of all the summary of product characteristics, in the form approved by the Member States, and the list of countries in which it is submitted the request.

B. Technical tab (summary of features

of the product)

The applicant will propose a summary of the product characteristics. In addition, the applicant shall provide one or more samples or mock-ups of the sale of the immunological veterinary medicinal product, together with a package leaflet, where necessary.

C. Expert reports

All aspects of the documentation must be provided with expert reports.

Each expert report shall consist of a critical assessment of the various tests or trials carried out in accordance with this royal decree and shall demonstrate all relevant data for the assessment. The expert shall indicate whether, in his opinion, the product concerned provides sufficient guarantees as regards quality, safety and efficacy.

A target summary will not be sufficient.

All important data will be summarized in an appendix to the expert's report, whenever possible in the form of tables or charts. This report and the summaries shall contain precise references to the information contained in the main documentation.

Each expert report will be prepared by a person with due training and experience. The expert will sign and date and attach a brief overview of the qualifications, training and professional experience of the expert. The professional relationship that the expert holds with the applicant shall be recorded.

PART 2

Analytical (physico-chemical, biological or microbiological) tests of immunological veterinary medicinal products

All analytical procedures will be in line with the most recent scientific developments and will be validated procedures; the results of the validation studies will be provided.

All analytical procedures shall be described in detail in order to enable them to be reproduced in the control tests carried out at the request of the competent authorities; it shall also be described with the details of any special equipment or equipment which may be used, accompanied by the description, where possible, of schemes. The formula of the reagents shall be supplemented, where appropriate, by the method of manufacture. In the case of analytical procedures included in the European Pharmacopoeia or in the pharmacopoeia of a Member State, this description may be replaced by a precise reference to the pharmacopoeia concerned.

A. Qualitative and quantitative composition

The data and documents to be attached to the marketing authorisation application shall be submitted in accordance with the following provisions.

1. Qualitative composition: "Qualitative composition" of the immunological veterinary medicinal product shall mean the designation or description of all its components:

the active principle or principles,

the components of the adjuvants,

the component or components of the excipient, whatever their nature or the amount used, including preservatives, stabilizers, emulsifiers, dyes, taste correctors, aromatic agents, markers, etc.,

the components of the pharmaceutical form administered to animals.

This information should be supplemented by any useful information on the packaging and, where appropriate, the type of closure, and the devices to be used for the use or administration of the package must be described in detail. immunological veterinary medicinal product and to be supplied together with it.

2. Description of the constituents of immunological veterinary medicinal products: In the case of products listed in the European Pharmacopoeia or, failing that, in the national pharmacopoeia of one of the Member States, the main name of the corresponding monograph, which shall be compulsory for all these substances, with reference to the pharmacopoeia concerned.

For the other products, the international common name recommended by the World Health Organization, which may be accompanied by another common name or, failing that, the exact scientific name.

Products without an international name or an exact scientific name shall be designated by reference to their origin and method of production, with any other useful observation being completed, if this is necessary, for colouring matters, the designation by the indicative 'E' attributed to them by Directive 78 /25/EEC.

3. Quantitative composition: To provide the quantitative composition of the active substances of an immunological veterinary medicinal product, it is necessary to specify whenever possible the number of micro-organisms, the protein content specified, the mass, the number of IU or units of biological activity, either per dose or per unit of volume, and, in respect of the adjuvant and the components of the excipient, the mass or volume of each of them, taking due account of the specified in section B.

The international units of biological activity that have been defined will be used.

The units of biological activity of which no published data exist shall be expressed in such a way as to provide unambiguous information on the activity of the ingredients, for example by exposing the immunological effect in which the based on the dose determination method.

4. Pharmaceutical development: The choice of composition, components and container shall be explained and shall be justified by scientific data relating to the development of galenic. Any overdosage should be indicated and justified. The efficacy of the storage system shall be demonstrated.

B. Description of the finished product manufacturing method

The description of the manufacturing method to accompany the marketing authorisation application shall be drawn up in such a way as to provide an appropriate description of the nature of the operations carried out.

For this purpose, this description must include at least:

the various stages of manufacturing (including purification processes) so that the reproducibility of the manufacturing process and the risks of negative effects on finished products can be assessed, such as the microbiological contamination,

in case of continuous manufacture, complete information on the measures taken to ensure the homogeneity and constancy of each batch of finished product,

substances that cannot be recovered throughout manufacturing,

data on the mixture, with the quantitative composition of all the substances used,

indication of the manufacturing phase in which samples are taken to perform controls during processing.

C. Production and control of starting materials

"Starting materials" means all components used in the production of the immunological veterinary medicinal product. The means of crops used in the production of the active substance are considered as a single starting material.

In the case of an active substance not described in the European Pharmacopoeia or in the pharmacopoeia of any Member State, or an active substance described in the European Pharmacopoeia or in the pharmacopoeia of a Member State, if prepares by a method which can leave impurities not mentioned in the pharmacopoeia monograph and whose quality cannot be adequately controlled by this monograph, which has been manufactured by a person other than the applicant, this (a) the manufacturer of the active ingredient may be provided directly to the competent authorities the detailed description of the manufacturing method, the quality control during the manufacturing process and the validation of the process. In this case, however, the manufacturer must provide the applicant with all the data which may be necessary for the latter to take responsibility for the medicinal product. The manufacturer shall undertake in writing before the applicant to ensure the constancy of the lots and not to modify the manufacturing process or specifications without informing him. The necessary data and documents shall be submitted to the competent authorities in support of such a modification request.

In the data and documents attached to the marketing authorisation application, the results of the tests relating to the quality control of all the components used shall be included. These data and documents shall be submitted in accordance with the following requirements.

1. Starting materials entered in the pharmacopoeias: The monographs of the European Pharmacopoeia shall be applicable to all the products listed therein.

For other products, each Member State may require the observance of its national pharmacopoeia in relation to the products manufactured in its territory.

The conformity of the components with regard to the requirements of the European Pharmacopoeia or the pharmacopoeia of one of the Member States shall be sufficient. In such cases, the description of the methods of analysis may be replaced by a detailed reference to the pharmacopoeia concerned.

When a substance is not described in the European Pharmacopoeia or in the relevant national pharmacopoeia, it may be permitted to refer to pharmacopoeas of third countries; in such a case, the monograph must be presented, accompanied, where necessary, by a translation of which the applicant shall be responsible.

In all cases, the colours must meet the requirements laid down in Directive 78 /25/EEC.

The systematic tests performed on each batch of starting materials shall be carried out as described in the application for marketing authorisation. If tests other than those mentioned in the pharmacopoeia are used, it must be proved that the raw materials correspond to the quality requirements of that pharmacopoeia.

In cases where the specification or other provisions contained in a monograph of the European Pharmacopoeia or in the national pharmacopoeia of a Member State are not sufficient to ensure the quality of the product, the competent authorities may require more appropriate specifications from the applicant for the marketing authorisation of the product.

The competent authorities shall inform the authorities responsible for the pharmacopoeia concerned thereof.

The applicant for the product marketing authorisation shall communicate to the authorities responsible for that pharmacopoeia the details of the alleged insufficiency and the additional specifications that have been provided.

When a starting material is not described in either the European Pharmacopoeia or the pharmacopoeia of a Member State, it is permissible to follow the monograph of the pharmacopoeia of a third country; in such cases, the applicant shall submit a copy of the monograph accompanied, where necessary, by the validation of the analytical procedures contained in the monograph and, where appropriate, a translation. In the case of active substances, the adequacy of the monograph must be demonstrated to adequately control the quality of these principles.

2. Starting materials not registered in a pharmacopoeia:

2.1 Biological source materials.

The description will be presented in the form of monograph.

Whenever possible, the production of vaccines shall be based on a batch system of inoculum and on recognised cell banks. In the case of production of immunological veterinary medicinal products consisting of serums, the origin, general health status and immunological status of the producing animals shall be indicated; defined mixtures of materials of item.

The origin and history of starting materials should be described and documented. In the case of starting materials derived from genetic engineering, this information shall include aspects such as the description of the cells or strains of departure, the construction of the expression vector (name, origin, function of the replicate, promoter stimulator and other regulatory elements), control of the DNA sequence or RNA inserted effectively, sequences of oligonucleotides of the plasmidic vector in the cells, plasmid used for the counter-fection, added genes or deleted, final construction biological properties and the genes expressed, number of copies and genetic stability.

The identity and possible presence of adventitious agents in all inoculum materials, including cell banks and the starting serum for the production of antisera, will be verified.

Information will be given on all substances of biological origin used at any stage of the manufacturing process. This information will include:

materials source data,

data on any transformation, purification or inactivation performed, as well as on the validation of these processes and the controls during them,

data on contamination detection tests performed with each batch of the substances.

If the presence of adventitious agents is detected or suspected, the corresponding material will be removed or used in very exceptional cases only if the subsequent treatment of the product guarantees the elimination or inactivation of such agents; this removal or inactivation must be demonstrated.

If cell banks are used, it will be necessary to demonstrate that the cell characteristics remain unchanged until the pass used directly in the production.

In the case of live attenuated vaccines, the stability of the attenuation characteristics of the inoculum must be demonstrated.

Where necessary, samples of the biological material of departure or of the reagents used in the test methods shall be provided to the competent authorities in order to enable those authorities to provide for the carrying out of the tests. of the necessary evidence of testing.

2.2 Non-biological origin materials: The description shall be presented in the form of monograph with the following headings:

the name of the starting material that meets the requirements of paragraph 2 of A shall be accompanied by its commercial or scientific synonyms,

the description of the starting material, established in a manner similar to that used in the European Pharmacopoeia descriptions,

the function of the starting material,

identification methods,

purity shall be described in relation to the total amount of foreseeable impurities, in particular those which may have a harmful effect and, where necessary, which may adversely affect the stability of the medicinal product or to distort the analytical results, taking into account the combination of substances referred to in the application. A brief description shall be given of the tests carried out to establish the purity of each batch of the starting material, any precautions which may be necessary during the storage of the starting material and, where appropriate, its period of validity.

D. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies

The applicant must demonstrate that the veterinary medicinal product has been manufactured in accordance with the explanatory note on how to minimise the risks of transmission of animal spongiform encephalopathy agents through the veterinary medicinal products and their updates, published by the European Commission in Volume 7 of its publication Rules on veterinary medicinal products in the European Community

E. Control tests performed

during production

1. The data and documents annexed to an application for a marketing authorisation shall include in particular data relating to the control tests carried out with the intermediate products in order to verify the constancy of the process of production and end product.

2. In the case of inactivated or detoxified vaccines, inactivation or detoxification shall be checked during each production run immediately after the inactivation or detoxification process is performed.

F. Testing of the finished product

The data and documents attached to the marketing authorisation application shall include those relating to the checks carried out on the finished product. Where there are appropriate monographs, if test methods and limits other than those mentioned in the monographs of the European Pharmacopoeia or, failing that, of the national pharmacopoeia of a Member State are used, the product must be shown to be finished, if tested according to these monographs, would meet the quality requirements laid down in that pharmacopoeia for the corresponding pharmaceutical form. The application for a marketing authorisation shall present a list of these tests to be carried out on representative samples of each batch of the finished product. The frequency of tests which are not carried out with each batch shall be indicated. Limits for approval will also be indicated.

1. General characteristics of the finished product: The tests of the finished product include certain controls of the general characteristics of the finished product, even if the tests have been carried out during the process of manufacturing.

These control tests shall, whenever appropriate, refer to the determination of the average masses and the maximum deviations, to the mechanical, physical, chemical or microbiological tests and to the physical characteristics such as the density, pH, refractive index, etc. In each individual case, the applicant shall establish the appropriate specifications and confidence limits for each of these characteristics.

2. Identification and determination of the active substance (s): In all tests, the description of the analysis techniques of the finished product shall be established in sufficient detail to enable it to be reproduced easily.

The determination of the biological activity of the active substance or principles shall be performed either with a representative sample of the manufacturing batch or with a given number of doses analysed in isolation.

If necessary, a specific identification test will also be performed.

In certain exceptional cases in which the determination of the active principles, to be very numerous or to be present only in very small proportions, requires very complex and difficult investigations in each batch of manufacture, the determination of one or more active substances in the finished product may be omitted, with the express condition that these determinations are carried out at intermediate stages of the production process which are as close as possible to the end of the process. This derogation shall not extend to the characterisation of such substances. This simplified technique shall be supplemented by a quantitative assessment method which enables the competent authorities to verify that the immunological veterinary medicinal product corresponds to its formula after placing on the market.

3. Identification and determination of the adjuvants: To the extent that test methods are available, the quantity and nature of the adjuvant and its components shall be verified in the finished product.

4. Identification and determination of the components of the excipient: To the extent necessary, the excipient or excipients shall be the subject of at least identification tests.

The proposed technique for the identification of colours should allow for the verification that these colours are authorised in accordance with Directive 78 /25/EEC.

The preservative agents must be subjected to a lower limit and upper limit test; any other component of the excipient which may produce an adverse reaction shall be subjected to a test. upper limit.

5. Safety tests: In addition to the results presented in accordance with the following paragraph, data on safety tests shall be provided. These tests shall preferably consist of overdosage studies carried out in at least one of the most sensitive target species and at least the recommended route of administration posing the greatest risk.

6. Sterility and purity tests: appropriate tests must be carried out to demonstrate the absence of contamination by adventitious agents or other substances, depending on the nature of the immunological veterinary medicinal product, the method and conditions of manufacturing.

7. Inactivation: When applicable, a test will be performed with the product in the final container to verify inactivation.

8. Residual moisture: Each batch of lyophilised product shall be subjected to a residual moisture determination test.

9. Batch constancy: In order to ensure that the efficacy of the product is reproducible between batches and to demonstrate compliance with the specifications, activity testing shall be carried out on the active principles based on in vitro or in-in-use methods. live, including suitable reference materials where possible, with each final mass in bulk or each batch of finished product, with appropriate confidence limits; in exceptional circumstances, the verification of the activity may be be carried out at an intermediate stage in the production process, as close as possible to the end of the production process. process.

G. Stability tests

The data and documents to be attached to the marketing authorisation application shall be submitted in accordance with the following indications.

The tests performed that have allowed the validity period proposed by the applicant to be determined shall be described.

These tests will always be real time studies, will be carried out with a sufficient number of batches produced according to the production process described and with products stored in the container or final packaging and will be included biological and physicochemical stability tests.

The findings will include the results of the analyses and justify the proposed period of validity in all proposed storage conditions.

In the case of premixtures for food, the necessary information on the period of validity of the product shall also be included in the different mixing stages, when mixed according to the instructions for use. recommended.

If a finished product has to be reconstituted prior to administration, details of the proposed validity periods for the reconstituted product shall be indicated in accordance with the instructions for use. Data shall be submitted to justify the proposed period of validity for the reconstituted product.

PART 3

Safety study

A. Introduction

Safety tests will show the potential risks that may arise from the immunological veterinary medicinal product under the proposed conditions of use in animals: these risks must be assessed in relation to the potential beneficial effects of the product.

When immunological veterinary medicinal products consist of live organisms, in particular those which may be disseminated by vaccinated animals, the potential risk to animals of the vaccine must be assessed. or any other species that may be exposed.

The data and documents accompanying the marketing authorisation application shall be submitted in accordance with the requirements of the following paragraph B.

Member States shall ensure that laboratory tests are carried out in accordance with the principles of good laboratory practice

B. General requirements

1. The safety tests shall be carried out on the target species.

2. The dose used shall consist of the quantity of product the use of which is recommended and containing the maximum activity or title considered in the application.

3. The samples used for the safety tests shall be taken from a batch or batches produced in accordance with the manufacturing process described in the marketing authorisation application.

C. Laboratory tests

1. Safety of single-dose administration: The immunological veterinary medicinal product shall be administered at the recommended dose and by all recommended routes of administration to animals of each species and category in which it is intended to be used, including animals of the minimum age of administration. Animals shall be observed and examined for signs of systematic and local reactions. Where appropriate, these studies will include detailed microscopic and macroscopic examination of the site of injection following the death of the animal. Other objective criteria, such as rectal temperature and production measurements, shall be recorded.

Animals will be observed and examined until more reactions can no longer be expected, but in all cases the observation and examination period will last at least 14 days from administration.

2. Safety of a single administration of an overdose: An overdose of the immunological veterinary medicinal product shall be administered for each recommended route of administration to animals of the most sensitive categories of the target species. Animals shall be observed and examined for signs of systematic and local reactions. Other objective criteria, such as rectal temperature and production measurements, shall be recorded.

Animals shall be observed and examined for a minimum period of 14 days from administration.

3. Safety of repeated administration of a single dose: It may be necessary to repeatedly administer a single dose to show the potential adverse effects induced by such administration. These tests shall be carried out with the most sensitive categories of the target species, using the recommended route of administration.

Animals will be observed and examined for a minimum period of 14 days from the last administration to detect possible signs of systemic and local reactions. Other objective criteria, such as rectal temperature and production measurements, shall be recorded.

4. Review of the reproductive function: An examination of the reproductive function shall be taken into account when there is data suggesting that the starting material from which the product is derived may be a potential risk factor. The reproductive function of males and females, pregnant and non-pregnant, shall be investigated at the recommended dose and using each of the recommended routes of administration. Potential harmful effects on progeny as well as teratogenic and abortive effects will also be investigated.

These studies may be part of the safety studies described in point 1.

5. Examination of the immunological functions: Where the immunological veterinary medicinal product may adversely affect the immune response of the vaccinated animal or its progeny, appropriate testing of the immunological functions shall be carried out.

6. Special requirements for live vaccines:

6.1 Transmission of the vaccine strain: The transmission of the vaccine strain from vaccinated target animals to the unvaccinated will be investigated using the recommended route of administration that can lead to the transmission of the vaccine strain. more likely. In addition, it may be necessary to investigate the transmission to non-target species that may be very sensitive to the live vaccine strain.

6.2 Distribution in the vaccinated animal: The presence of the microorganism in the faeces, urine, milk, eggs and oral, nasal and other secretions will be investigated. In addition, it may be necessary to carry out studies on the distribution of the vaccine strain in the body, paying particular attention to the favorite places of replication of the micro-organism. In the case of live vaccines for well known zoonotic diseases, intended for food-producing animals, these studies shall be compulsory.

6.3 Reversion to the virulence of attenuated vaccines:

Reversal to virulence will be investigated with material from the pass that is less attenuated between the original inoculum and the final product. The initial vaccination will be carried out following the recommended route of administration that can most likely lead to reversal of virulence. At least five animal-serial passes of the target species shall be carried out. If this is not technically possible because the micro-organism does not replicate properly, as many passes will be carried out as possible in the target species. Where necessary, the in vitro propagation of the micro-organism may be carried out between countries in vivo. The passes will be performed by the route of administration that can most likely produce the reversal to virulence.

6.4 Biological properties of the vaccine strain:

Other tests may be required to determine as accurately as possible the intrinsic biological properties of the vaccine strain (e.g., neurotropism).

6.5 Recomination or Genomic Redistribution of Strains:

The probability of recombination or genomic redistribution with wild or other strains will be discussed.

7. Study of waste: In the case of immunological veterinary medicinal products, it will not normally be necessary to carry out a waste study. However, where adjuvants or preservatives are used in the manufacture of immunological veterinary medicinal products, consideration must be given to the possibility of any residue remaining in the food. If necessary, the effects of such residues must be investigated. In addition, in the case of live vaccines for zoonotic diseases, it may be necessary to determine the residues at the site of the injection, in addition to the studies described in point 6.2.

A proposal for the time to delete will be submitted and its validity discussed in relation to the waste studies that have been carried out.

8. Interactions: Any known interaction with other products will be indicated.

D. Field Studies

Except duly justified cases, results from laboratory studies shall be completed with data supporting them from field studies.

E. Ecotoxicity

The objective of the study of the ecotoxicity of an immunological veterinary medicinal product is to assess the harmful effects of the use of the product on the environment, as well as to identify precautionary measures. may be necessary to reduce such risks.

An ecotoxicity assessment shall be required in the case of any application for the marketing authorisation of an immunological veterinary medicinal product.

This evaluation should normally be performed in two phases.

The first phase of the assessment shall be carried out in all cases; the investigator shall assess the possible extent of the exposure of the environment to the product or its relevant active substances or metabolites, taking into account:

the target species and the recommended type of use (for example, collective medication or medication for specific animals),

the method of administration, especially the extent to which the product is likely to pass directly into the environment,

the possible excretion of the product or its active substances or important metabolites into the environment by the treated animals; persistence in such excreta,

removing residual or unused products.

When the conclusions of the first phase indicate the possible exposure of the environment to the product, the applicant will move to the second phase and assess the possible ecotoxicity of the product. For this purpose, account shall be taken of the extent and duration of the exposure of the environment to the product and the information on the physicochemical, pharmacological or toxicological properties of the compound which has been obtained during the performance. of the other tests required under this royal decree. Where necessary, further studies on the impact of the product (soil, water, air, aquatic systems, non-target organisms) shall be carried out.

These complementary studies will be carried out in accordance with the test protocols set out in Annex V to Directive 67 /548/EEC or, where a particular point is not adequately covered by these protocols, according to other internationally recognised immunological veterinary medicinal products, the active substances or the metabolites excreted as appropriate. The number and type of tests and the criteria for evaluating them will depend on the state of the science at the time the application is submitted.

PART 4

Efficacy tests

A. Introduction

1. The purpose of the tests described in this part is to demonstrate or confirm the efficacy of the immunological veterinary medicinal product. All statements made by the applicant in relation to the properties, effects and use of the medicinal product shall be fully justified by the results of specific tests included in the application for authorisation of the medicinal product. marketing.

2. The data and documents to be attached to the marketing authorisation application shall comply with the following provisions.

3. All veterinary clinical trials shall be carried out in accordance with a detailed test protocol to be recorded in writing before the start of the test. During the preparation of any test protocol and throughout the test protocol, the welfare of the test animals, which shall be the subject of veterinary supervision, shall be taken into account at all times.

Preestablished written procedures concerning the organisation, performance, data collection, documentation and testing of clinical trials shall be systematically required.

4. Before starting any test, it will be necessary to obtain and document the consent with knowledge of the cause of the owner of the animals to be used in the test. In particular, the owner of the animals shall be informed in writing of the consequences of the participation in the test with regard to the subsequent destination of the treated animals or the production of foodstuffs from the same. A copy of that notification, dated and endorsed by the owner of the animal, shall be included in the test documentation.

5. Unless the test is performed according to a blind method. In all cases, the labelling shall be clearly and indelibly marked as "exclusive use in veterinary clinical trials".

B. General requirements

1. The selection of vaccine strains shall be based on epizootic data.

2. The efficacy tests performed in the laboratory shall be controlled tests, with untreated control animals.

In general, these tests must be accompanied by tests carried out under field conditions, with untreated control animals.

All tests shall be described in sufficient detail to enable them to be reproduced in control tests, carried out at the request of the competent authorities. The investigator shall demonstrate the validity of all the techniques used. All results shall be presented as accurately as possible.

All results obtained will be indicated, whether they are favorable or not.

3. The efficacy of an immunological veterinary medicinal product shall be demonstrated in relation to each category of each target species whose vaccination is recommended, using each of the recommended routes of administration and following the dosage. proposal. The effect on the effectiveness of a vaccine should be adequately assessed for the passively acquired antibodies and those derived from the mother. Any declaration concerning the appearance and duration of the protection shall be based on data from these tests.

4. The efficacy of each component of immunological veterinary medicinal products which are multivalent or associated shall be demonstrated. If it is recommended that the product be administered in association with another veterinary medicinal product or at the same time as the veterinary medicinal product, it is necessary to demonstrate its compatibility.

5. Whenever a product is part of a vaccination scheme recommended by the applicant, the inductor or recall effect or the contribution of the medicinal product to the efficacy of the scheme as a whole shall be demonstrated.

6. The dose to be used shall be that quantity of product the use of which is recommended and containing the minimum activity or concentration for which the application is submitted.

7. The samples used in the efficacy tests shall be taken from a batch or batches produced in accordance with the manufacturing process described in the marketing authorisation application.

8. In the case of diagnostic immunological veterinary medicinal products applied to animals, the applicant shall indicate how the reactions caused by the product have to be interpreted.

C. Laboratory tests

1. In principle, the demonstration of efficacy must be carried out under perfectly controlled laboratory conditions by means of a provocation test following the administration of the immunological veterinary medicinal product to the target species in the recommended conditions of use. As far as possible, the conditions under which the provocation test will be performed should be similar to the natural conditions of the infection, for example with regard to the quantity of the provocation micro-organisms and the route of administration.

2. If possible, the immune mechanism (humour/cell-mediated, general/local immunoglobulins) to be triggered after administration of the immunological veterinary medicinal product to target species should be specified and documented. following the recommended route of administration.

D. Field Tests

1. Unless justified, the results of the laboratory tests shall be supplemented by data from field tests.

2. If the laboratory tests cannot demonstrate the effectiveness, the exclusive performance of field tests may be accepted.

Data and documents relating to the safety tests and efficacy of immunological veterinary medicinal products

A. Introduction

As in any scientific work, the dossier of safety and efficacy studies shall include an introduction in which the object is defined and the tests that have been carried out in accordance with Parts 3 and 4 shall be indicated, as well as a summary with bibliographic references. The omission of any test or test collected in Parts 3 and 4 shall be reported and discussed.

B. Laboratory studies

The following data and documents should be submitted for each study:

1) summary;

2) name of the body that has conducted the studies;

3) detailed experimental protocol with a description of the methods, equipment and materials used, data such as the species, breed or lineage of the animals, categories of animals, their provenance, identification and number, housing and food conditions (specifying aspects such as whether they were free of specific pathogens or specific antibodies, or the nature and quantity of any additives present in the feed), dose, route, plan and dates administration, description of the statistical methods used;

4) in the case of the test animals, if they have received a placebo or if they have not received any treatment;

5) all general and individual observations and the results obtained (with typical means and deviations), whether favorable or unfavorable. The data should be described in sufficient detail to allow the critical evaluation of the results, regardless of the interpretation by the author. The primary data shall be presented in the form of tables. For explanation and illustration, the results may be accompanied by reproductions of records, photomicrographs, etc.;

6) the nature, frequency and duration of adverse reactions observed;

7) the number of animals removed from the studies before the completion of the studies; causes of such withdrawal;

8) statistical analysis of the results, when required by the test program, and differences between the data;

9) occurrence and course of any intercurrent disease;

10) all details concerning the medicinal products (other than the test product) whose administration was necessary during the study;

11) objective discussion of the results obtained, from which conclusions are drawn on the safety and efficacy of the product.

C. Field Studies

The data on field studies should be sufficiently detailed to allow for the formulation of an objective judgment. They will include the following:

1) summary;

2) name, address, function and rating of the investigator in charge;

3) place and date of administration, name and address of the owner of the animal or animals;

4) test protocol data, with a description of the methods, equipment and materials used, with aspects such as the route of administration, the administration schedule, the dose, the categories of animals, the duration of the test observation, serological response and other research carried out on animals after administration;

5) in the case of a witness, if they have received a placebo or have not received any treatment;

6) identification of treated and witness animals (collective or individual, as appropriate) as species, race or lineage, age, weight, sex and physiological status;

7) brief description of the breeding and feeding method, specifying the nature and quantity of any additives included in the feed;

8) all data relating to observations, production of animals and results (with average and standard deviation); individual data shall be indicated when tests and measures have been carried out with different individuals;

9) all observations and results of the studies, whether favourable or unfavourable, with a full statement of the observations and results of the objective tests of activity required to assess the product; the techniques used must be specified and the significance of any variation in the results to be explained;

10) effect on the production of animals (e.g. egg laying, milk production, reproductive function);

11) number of animals removed from the studies prior to completion of the studies and cause of such withdrawal;

12) nature, frequency and duration of adverse reactions observed;

13) occurrence and course of any intercurrent disease;

14) all data relating to medicinal products (other than the product under study) which have been administered before or at the same time as the product concerned or during the observation period; data on possible interactions observed;

15) objective discussion of the results obtained, from which conclusions on the safety and efficacy of the medicinal product are derived.

D. General conclusions

The general conclusions on all the results of the tests and trials carried out in accordance with Parts 3 and 4 shall be indicated. These conclusions shall contain an objective discussion of all the results obtained and shall lead to a conclusion on the safety and efficacy of the immunological veterinary medicinal product.

E. Bibliography

A detailed list of the bibliographic citations included in the summary referred to in paragraph A. will be presented.

ANNEX II

Product Characteristics or Summary of Product Characteristics

The product characteristics summary or technical tab will contain the following data, in the order listed below:

1. name of the veterinary medicinal product followed by the dosage/concentration and the pharmaceutical form;

2. qualitative and quantitative composition, in terms of active substances and components of the excipient, the knowledge of which is necessary for the correct administration of the medicinal product; the official Spanish denominations or the international common names or chemical names;

3. pharmaceutical form;

4. clinical data:

4.1 target species,

4.2 indications of use, for each of the target species,

4.3 contraindications,

4.4 special warnings for each target species,

4.5 special precautions for use, including specific precautions to be taken by the person administering the medicinal product to animals,

4.6 adverse reactions (frequency and severity),

4.7 use during pregnancy, breast-feeding, or breast-feeding,

4.8 interactions with other medicinal products and other forms of interaction,

4.9 posology and route of administration,

4.10 overdose (symptoms, emergency measures, antidotes), if necessary,

4.11 wait time for different foods, including those for which the timeout is zero days,

5. pharmacological/immunological properties:

5.1 pharmacodynamic properties, where applicable,

5.2 pharmacokinetic properties, where appropriate,

6. pharmaceutical data:

6.1 list of excipients,

6.2 main incompatibilities,

6.3 period of validity of the medicinal product, if necessary after reconstitution of the medicinal product or when the primary packaging is first opened,

6.4 special precautions for storage,

6.5 nature and composition of the primary packaging,

6.6 special precautions to be taken to remove the unused veterinary medicinal product or, where appropriate, waste from its use;

7. marketing authorisation holder;

8. number or numbers of the marketing authorisation;

9. the date of the first authorisation or the date of renewal of the authorisation;

10. date of the revision of the text.

ANNEX III

Labelling and Package Leaflet

Part One. Information to be included in the packaging/labels

1. The name of the veterinary medicinal product, followed by dosage/concentration and pharmaceutical form. Where the medicinal product contains only one active substance and its name is a name of fantasy, the official Spanish name or the common name of the active substance shall be indicated, following the name of the name and between parenthesis. The official Spanish name or the common name, not forming part of the name of the medicinal product, may also be included in the line following that of the medicinal product.

2. The qualitative and quantitative composition of the active substances and other substances by dose or by the method of administration, for a given volume or weight, by identifying them with their respective Spanish official names or, in their defect, with international denominations or in default by their scientific name.

3. The number of the manufacturing batch/s.

4. The number of the marketing authorization.

5. The name or business name and the registered office or registered office of the marketing authorisation holder, the manufacturer (batch release in the European economic space for third-country manufacturers) if it differs from the holder and, where appropriate, the representative of the marketing authorisation holder.

6. The animal species to which the veterinary medicinal product is intended, posology on the basis of those species, mode and in cases where the route of administration is necessary. Indications for correct administration, if there are reasons. A free space should be provided to indicate the prescribed dosage.

7. The waiting time for veterinary medicinal products to be administered to food-producing animals, for all the species concerned and for the different foods concerned (meat, eggs, milk, honey), including those whose timeout is zero.

8. The expiration date, in understandable language; it will be set with digits for the month and year.

9. special precautions for storage, if appropriate in the space reserved for specific national requirements, the symbol of the cold shall appear, where appropriate.

10. Information imposed in relation to the prescription and dispensing, if any.

11. The indication 'for veterinary use' shall be entered. For medicinal products subject to prescription, the indication to be entered shall be 'for veterinary use-medicinal product subject to veterinary prescription'.

12. The pharmaceutical form and the content by weight, by volume or in taking units, may be indicated only on the packaging.

13. In so far as they affect the qualitative and quantitative composition of the active substances of veterinary medicinal products, the provisions of Section A of Part II of Annex I shall apply to the particulars provided for in paragraph 2 of this Article. the first part of Annex III.

14. The information provided for in paragraph 1 shall be drawn up in the box and in the package of medicinal products at least in Spanish.

15. For medicinal products authorised in accordance with the provisions of Regulation (EC) No 726/2004, the Agency shall, on the external packaging, authorise additional information relating to the distribution, possession, sale or sale of medicinal products. possible precautionary measures in accordance with the provisions on conditioning material of this royal decree.

16. In the absence of outer packaging, all the data set out in this Annex shall be indicated in the primary packaging.

17. In the case of ampoules, the data referred to in the first part of this Annex III shall be indicated on the outer packaging, only the following data shall be required for packaging or labels:

(a) the name of the veterinary medicinal product,

b) the amount of the active principles,

c) the administration path,

d) the number of the manufacturing batch,

e) the expiration date,

f) the mention "of veterinary use".

18. Where primary conditioners of small size other than ampoules and containing a single dose, and on which it is impossible to indicate the data provided for in this Annex III, the requirements of the paragraphs shall apply only to the outer packaging.

Part Two. Minimum information to be included in the package leaflet of the veterinary medicinal product

1. Name or business name and address or registered office of the marketing authorisation holder and of the manufacturer (for medicinal products manufactured in third countries shall be the release of the lot in the European economic area) and, if applicable, of the representative of the marketing authorisation holder.

2. Name of the veterinary medicinal product followed by dosage/concentration and pharmaceutical form. Where the medicinal product contains only an active ingredient and its name is a name of fantasy, the official Spanish name or the common name shall be indicated. Where the medicinal product is authorised under the procedure laid down in Chapter VIII of Title I, with different names in different Member States concerned, a list of the names authorised in each Member State shall be provided. member.

The official Spanish denominations or international denominations recommended by the World Health Organization shall be used, provided that such names exist.

3. Qualitative and quantitative composition in terms of active substances and other substances.

4. Usage indications.

5. Contraindications and adverse reactions, personal registration number to the extent that such information is necessary for the use of the veterinary medicinal product.

6. Target species, posology on the basis of these species, mode and route of administration, indications for correct administration, if there are reasons.

7. Wait times even when they are zero days, for veterinary medicinal products to be administered to food-producing animals for human consumption.

8. Special precautions for storage if there are grounds;

9. Indications imposed if there are grounds, in the marketing authorisation for the holder of the same, to mention in the immediate packaging, in the outer packaging, or both, and in the package leaflet, when the latter is required, other indications essential for safety or for the protection of health, including special precautions for use and other warnings resulting from clinical and pharmacological tests.

10. Special precautions to be taken to remove the unused veterinary medicinal product or, where appropriate, residues resulting from its use, where appropriate.

Part Three. Symbols, acronyms, and legends

The packaging of veterinary medicinal products shall include the following symbols and requirements in the upper right corner, as appropriate:

Imagen: img/disp/2008/193/13682_001.png

The following acronyms should also be included as appropriate:

AV, when the medication has to be administered exclusively by the veterinarian

In the first two cases, the following legends must be listed:

"Exclusive administration by the veterinarian"

In all cases, the legend must be listed:

"VETERINARY USE".

In the particular case of medicated premixtures the legend must be shown:

Drug premixtures for feed.