LegalizeCommission Delegated Regulation (EU) 2021/805 of 8 March 2021 amending Annex II to Regulation (EU) 2019/6 of the European Parliament and of the Council (Text with EEA relevance)
This is the act as published. Later amendments are not folded into the text below: each one is a separate act in this repository and an entry in this law's history.
Unless otherwise justified, results from pre-clinical studies shall be supplemented with data from clinical trials, using batches representative of the manufacturing process described in the marketing authorisation application. Both safety and efficacy may be investigated in the same clinical trials.
IIIb.3D. Environmental risk assessment
| (1) | An environmental risk assessment shall be performed to assess the potential harmful effects, which the use of the veterinary medicinal product may cause to the environment and to identify the risk of such effects. The assessment shall also identify any precautionary measures which may be necessary to reduce such risk. | |
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| (2) | This assessment consists of two phases. The first phase of the assessment shall always be performed. The details of the assessment shall be provided in accordance with guidance published by the Agency. It shall indicate the potential exposure of the environment to the product and the level of risk associated with any such exposure, taking into account in particular the following items: (a) the target animal species and the proposed pattern of use; (b) the route and method of administration, in particular the likely extent to which the product will enter directly into the environmental system; (c) the possible excretion or secretion of the product, its active substances into the environment by treated animals, persistence in such excreta or secreta; (d) the disposal of unused or waste product. | |
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| (3) | In the case of live vaccine strains which may be zoonotic, the risk to humans shall be assessed. | |
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| (4) | Where the conclusions of the first phase indicate a relevant potential risk for the environment of the product, the applicant shall proceed to the second phase and evaluate the potential risk(s) that the veterinary medicinal product might pose to the environment. Where necessary, further investigations on the impact of the product (soil, water, air, aquatic systems, non-target organisms) shall be carried out. | |
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| (5) | For DNA vaccines, a specific safety concern is the potential risk of migration of the DNA to gonadal tissues and potential DNA transfer into germ line cells of vaccinated male and female animals and thus potential transmission to offspring. The applicant shall evaluate and discuss potential risk(s) such immunological veterinary medicinal products might pose on human health and the environment (including plants and animals). If potential risk(s) are identified, investigations on the impact of the vaccine depending on its use in companion animals or in food producing animals shall be carried out to provide information on this point. |
IIIb.3E. Assessment required for veterinary medicinal products containing or consisting of genetically modified organisms
| (1) | In the case of veterinary medicinal products containing or consisting of genetically modified organisms (GMOs) the application shall also be accompanied by the documents required under Article 2 and Part C of Directive 2001/18/EC and the specific guidance dealing with GMOs. | |
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| (2) | Potential adverse effects on human health and the environment, which may occur through gene transfer from GMOs to other organisms or arise from genetic modifications, shall be accurately assessed on a case-by-case basis. The objective of such an environmental risk assessment is, to identify and evaluate potential direct and indirect, immediate or delayed adverse effects of the GMO on human health and the environment (including plants and animals) and shall be carried out in accordance with the principles of Annex II to Directive 2001/18/EC. |
IIIb.3F. Residue tests to be included in the pre-clinical studies
| (1) | For immunological veterinary medicinal products, it will normally not be necessary to undertake a study of residues. | |
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| (2) | Where antibiotics, adjuvants, preservatives or any other excipient are used in the manufacture of immunological veterinary medicinal products intended for food producing animals and/or are included in the final formulation, consideration shall be given to the possibility of consumer exposure to residues in foodstuffs derived from treated animals and compliance with MRLs legislation. Consumer safety implications arising from their potential presence in the finished product shall be addressed. | |
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| (3) | In the case of live vaccines for well-established zoonotic diseases, in addition to the studies of dissemination, the determination of residual vaccine organisms at the injection site may be required. If necessary, the effects of such residues shall be investigated. | |
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| (4) | A proposal for a withdrawal period shall be made and its adequacy shall be discussed in relation to any residue studies which have been undertaken. |
IIIb.4. Part 4: Efficacy documentation (pre-clinical studies and clinical trial(s))
IIIb.4A. General requirements
| (1) | The following general requirements shall be complied with: (a) the efficacy studies shall be in line with the general European Pharmacopeia requirements; Deviations shall be justified. (b) the primary parameter on which determination of efficacy is based needs to be defined by the investigator at the time of study design and shall not be changed after the study is completed; (c) the planned statistical analysis shall be described in detail in the study protocols; (d) the choice of antigens or vaccine strains shall be justified on the basis of epizoological data; (e) efficacy trials carried out in the laboratory shall be controlled trials, including untreated control animals unless this is not justified for animal welfare reasons and efficacy can be otherwise demonstrated. | |
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| (2) | In general, pre-clinical studies shall be supported by trials carried out in field conditions. When pre-clinical studies fully support the claims made in the summary of product characteristics, trials carried out in field conditions are not required. Unless otherwise justified, results from pre-clinical studies shall be supplemented with data from clinical trials, using batches representative of the manufacturing process described in the marketing authorisation application. Both safety and efficacy may be investigated in the same clinical trials. | |
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| (3) | All trials shall be described in sufficient detail so as to be properly assessed by the competent authorities. The validity of all techniques used in the trial shall be demonstrated. | |
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| (4) | All results obtained, whether favourable or unfavourable, shall be reported: (a) The efficacy of an immunological veterinary medicinal product shall be demonstrated for each category of target animal species in which its use is recommended, by each recommended route and method of administration and using the proposed schedule of administration. Unless otherwise justified, the onset and duration of immunity shall be established and supported by data from trials. (b) The influence of passively acquired maternally derived antibodies on the efficacy of vaccines when administered to animals at an age at which maternally acquired immunity is still present shall be adequately evaluated, if appropriate. (c) The efficacy of each of the components of multivalent and combined immunological veterinary medicinal products shall be demonstrated. If the product is recommended for administration in combination with or at the same time as another veterinary medicinal product, to the efficacy of the association shall be demonstrated by appropriate studies. Any known interactions with any other veterinary medicinal products shall be described. (d) Whenever a product forms part of a vaccination scheme recommended by the applicant, the priming or booster effect or the contribution of the veterinary immunological product to the efficacy of the scheme as a whole shall be demonstrated. (e) The dose to be used shall be the quantity of the product to be recommended for use and the batch used for efficacy testing shall be taken from a batch or batches produced according to the manufacturing process described in Part 2 of the application. (f) For diagnostic immunological veterinary medicinal products administered to animals, the applicant shall indicate how reactions to the product are to be interpreted. (g) For vaccines intended to allow a distinction between vaccinated and infected animals (marker vaccines), where the efficacy claim is reliant on in vitro diagnostic tests, sufficient data on the diagnostic tests shall be provided to allow adequate assessment of the claims related to the marker properties. |
IIIb.4B. Pre-clinical studies
| (1) | In principle, demonstration of efficacy shall be undertaken under well-controlled laboratory conditions by challenge after administration of the immunological veterinary medicinal product to the target animal under the recommended conditions of use. Insofar as possible, the conditions under which the challenge is carried out shall reflect the natural conditions for infection. Details of the challenge strain and its relevance shall be provided. | |
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| (2) | For live vaccines, the product used for efficacy testing shall be taken from a batch or batches containing the minimum titre or potency. For other products, product from batches containing the minimum active content or potency expected at the end of the period of validity shall be used, unless otherwise justified. | |
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| (3) | If possible, the immune mechanism (cell-mediated/humoral, local/general classes of immunoglobulin) which is initiated after the administration of the immunological veterinary medicinal product to target animals by the recommended route of administration shall be specified and documented. | |
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| (4) | The following shall be provided for all pre-clinical studies: (a) a summary; (b) a statement of compliance with good laboratory practice for pre-clinical studies, where applicable; (c) the name of the body having carried out the studies; (d) a detailed experimental protocol giving a description of the methods, apparatus and materials used, details such as species or breed of animals, categories of animals, where they were obtained, their identification and number, the conditions under which they were housed and fed (stating, inter alia, whether they were free from any specified pathogens and/or specified antibodies, the nature and quantity of any additives contained in the feed), dose, route, schedule and dates of administration, a description and a justification of the statistical methods used; (e) in the case of control animals, whether they received a placebo or no treatment; (f) in the case of treated animals and, where appropriate, whether they received the test product or another product authorised in the Union; (g) all general and individual observations and results obtained (with averages and standard deviations), whether favourable or unfavourable. The data shall be described in sufficient detail to allow the results to be critically evaluated independently of their interpretation by the author. The individual data shall be presented in tabular form. By way of explanation and illustration, the results may be accompanied by reproductions of recordings, photomicrographs, etc.; (h) the nature, frequency and duration of observed adverse reactions; (i) the number of animals withdrawn prematurely from the studies and reasons for such withdrawal; (j) a statistical analysis of the results, where such is called for by the test programme, and variance within the data; (k) occurrence and course of any intercurrent disease; (l) all details concerning veterinary medicinal products (other than the product under study), the administration of which was necessary during the course of the study; (m) any other observations and deviations from the protocol and possible impact on the results; (n) an objective discussion of the results obtained, leading to conclusions on the safety and efficacy of the product. |
IIIb.4C. Clinical trials
| (1) | Unless otherwise justified, results from pre-clinical studies shall be supplemented with data from field trials, using batches representative of the manufacturing process described in the marketing authorisation application. Both safety and efficacy may be investigated in the same field trial. | |
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| (2) | Where pre-clinical studies cannot be supportive of efficacy, the performance of field trials alone may be acceptable. | |
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| (3) | Particulars concerning field trials shall be sufficiently detailed to enable an objective judgement to be made. They shall include the following: (a) a summary; (b) a statement of compliance with good clinical practice; (c) name, address, function and qualifications of the investigator in charge; (d) place and date of administration, identity code that may be linked to the name and address of the owner of the animal(s); (e) details of the trial protocol, giving a description of the methods, apparatus and materials used, details such as the route and method of administration, the schedule of administration, the dose, the categories of animals, the duration of observation, the serological response and other investigations carried out on the animals after administration; (f) in the case of control animals, whether they received a placebo, a competitor product or no treatment; (g) identification of the treated and control animals (collective or individual, as appropriate), such as species, breeds or strains, age, weight, sex, physiological status; (h) a brief description of the method of rearing and feeding, stating the nature and quantity of any additives contained in the feed; (i) all the particulars on observations, performances and results (with averages and standard deviation); individual data shall be indicated when tests and measurements on individuals have been carried out; (j) a statistical analysis of the results, where such is called for by the test programme, and variance within the data; (k) all observations and results of the trials, whether favourable or unfavourable, with a full statement of the observations and the results of the objective tests of activity required to evaluate the product; the techniques used shall be specified and the significance of any variations in the results explained; (l) effects on the animals’ performance; (m) the number of animals withdrawn prematurely from the trials and reasons for such withdrawal; (n) the nature, frequency and duration of observed adverse reactions; (o) occurrence and course of any intercurrent disease; (p) all details concerning veterinary medicinal products (other than the product under study) which have been administered either prior to or concurrently with the test product or during the observation period; details of any interactions observed; (q) any other observations and deviations for the protocol and possible impact on the results; (r) an objective discussion of the results obtained, leading to conclusions on the safety and efficacy of the product. |
SECTION IV
REQUIREMENTS FOR SPECIFIC MARKETING AUTHORISATION APPLICATIONS
IV.1. Applications for generic veterinary medicinal products
| IV.1.1. | Applications based on Article 18 (generic veterinary medicinal products) shall contain the data referred to in Parts 1 and 2 of Section II of this Annex. If required, pursuant to Article 18(7) an environmental risk assessment shall be included. In addition, the dossier shall contain data demonstrating that the product has the same qualitative and quantitative composition in active substance(s) and the same pharmaceutical form as the reference medicinal product; and data, showing bioequivalence with the reference medicinal product or a justification as to why such studies were not performed with reference to established guidance. All immediate-release oral pharmaceutical forms shall be considered to be the same pharmaceutical form. For biological (including immunological) veterinary medicinal products, the standard generic approach is in principle not considered appropriate, and a hybrid approach shall be followed (see Part IV.2.). | |
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| IV.1.2. | For generic veterinary medicinal products, the critical expert reports on safety and efficacy shall particularly focus on the following elements: (a) the grounds for claiming bioequivalence; (b) a summary of impurities present in batches of the active substance(s) as well as those of the finished medicinal product (and where relevant decomposition products arising during storage) together with an evaluation of those impurities; (c) an evaluation of the bioequivalence studies or other information that may provide support for claiming bioequivalence in accordance with relevant guidance published by the Agency; (d) any additional data in order to demonstrate the equivalence of safety and efficacy properties of different salts, esters or derivatives of an authorised active substance; (e) a review of the user safety risk assessment focusing on differences between the generic and reference veterinary medicinal products (for example, composition in excipients); (f) a review of environmental risk assessment, where relevant. | |
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| IV.1.3. | For a generic veterinary medicinal product application containing an antimicrobial substance, information about the level of resistance, as known from bibliographic data, shall be provided. | |
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| IV.1.4. | For a generic veterinary medicinal product containing an antiparasitic substance, information about the level of resistance, as known from bibliographic data, shall be provided. | |
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| IV.1.5. | For generic veterinary medicinal products intended to be administered by intramuscular, subcutaneous or transdermal routes, the following additional data shall be provided: (a) evidence to demonstrate equivalent or differing depletion of residues from the administration site, which may be substantiated by appropriate residue depletion studies; (b) evidence to demonstrate target animal tolerance at the administration site, which may be substantiated by appropriate target animal tolerance studies. |
IV.2. Applications for hybrid veterinary medicinal products
| IV.2.1. | Applications based on Article 19 (hybrid veterinary medicinal products) concern veterinary medicinal products, which are similar to a reference veterinary medicinal product, but which do not meet the conditions in the definition of generic veterinary medicinal product. | |
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| IV.2.2. | For such applications, the following information shall be supplied: (a) all the data referred to in Parts 1 and 2 of Sections II or III, as appropriate, of this Annex; (b) for Parts 3 and 4 of the dossier, hybrid applications may rely in part on the results of the appropriate safety, residue, pre-clinical studies and clinical trials for an already authorised reference veterinary medicinal product, and in part on new data. New data shall include a user safety risk assessment and an environmental risk assessment in accordance with Article 18(7), if applicable. In addition, for relevant products (for example, antimicrobials, antiparasitics) the risk of development of resistance shall be addressed, if applicable. | |
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| IV.2.3. | In the case of biological (including immunological) veterinary medicinal products, a comprehensive comparability review, addressing the quality, safety and efficacy part shall be provided. | |
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| IV.2.4. | Where reference is made to data originating from another authorised veterinary medicinal product, a justification for the use and relevance of those data for the new product shall be provided. | |
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| IV.2.5. | The extent of new data required to support safety and efficacy will depend on the specific characteristics of the individual new product, and its differences to the reference veterinary medicinal product, and shall be determined on a case-by-case basis. New pre-clinical and clinical data for the new product shall be presented for all aspects where the reference veterinary medicinal product does not provide relevant support. | |
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| IV.2.6. | If new studies are conducted with batches of a reference veterinary medicinal product authorised in a third country, the applicant shall demonstrate that the reference veterinary medicinal product has been authorised in accordance with requirements equivalent to those established in the Union, and are so highly similar that they may substitute each other in the pre-clinical studies or clinical trials. |
IV.3. Applications for combination veterinary medicinal products
| IV.3.1. | An application for a fixed combination product with individual active substances, which have already been the object of a marketing authorisation for a veterinary medicinal product in the EEA, shall be submitted under Article 20. A fixed combination product containing at least one new active substance which has not yet been authorised for a veterinary medicinal product in the EEA, shall be submitted under Article 8. | |
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| IV.3.2. | For applications submitted under Article 20, a full dossier containing Parts 1, 2, 3 and 4 shall be provided. | |
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| IV.3.3. | A sound scientific justification based on valid therapeutic principles for the combination of active substances, including clinical data, shall be provided, which demonstrates the need for and contribution of all active substances at the moment of treatment. | |
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| IV.3.4. | In general, all the data on the safety and efficacy shall be provided for the fixed combination product, and safety and efficacy data for the individual active substances alone are not required, except to clarify their individual pharmacological properties. | |
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| IV.3.5. | If data on the safety and efficacy of an individual known active substance are available to the applicant with sufficient amount of detail, those data could be provided to obviate the need for some studies with the fixed combination, or contributing relevant information. In that case, possible interaction between active substances shall also be investigated. | |
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| IV.3.6. | User safety assessment, environmental risk assessment, residues depletion studies, and clinical studies shall be conducted with the fixed combination product. | |
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| IV.3.7. | Unless the omission is justified, a target animal safety study with the final formulation shall be provided. |
IV.4. Applications based on informed consent
| IV.4.1. | Applications based on Article 21 concern products with identical composition, pharmaceutical form and manufacturing process (including raw and starting materials, process parameters and manufacturing sites) as the already authorised veterinary medicinal products. | |
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| IV.4.2. | The dossier for such applications shall only include data for Part 1A and 1B, as described in Annex I (points 1 to 6.4), provided that the marketing authorisation holder for the already authorised veterinary medicinal product has given the applicant his written consent to refer to the content of Parts 1C, 2, 3 and 4 of the dossier of that product. In that case, there is also no need to submit quality, safety and efficacy critical expert reports. The applicant shall provide proof of the written consent with their application. |
IV.5. Applications based on bibliographic data
| IV.5.1. | For veterinary medicinal products for which the active substance(s) has or have been in well-established veterinary use as referred to in Article 22, with recognised efficacy and an acceptable level of safety, the following specific rules shall apply. | |
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| IV.5.2. | A full dossier (containing Parts 1, 2, 3 and 4) shall be provided. The applicant shall submit Parts 1 and 2 as described in this Annex. For Parts 3 and 4, a detailed scientific bibliography together with information demonstrating the appropriate bridging between bibliographic references and the veterinary medicinal product shall be submitted to address safety and efficacy. The bibliographic data may need to be complemented by some documentation specific to the product, for example, user safety and environmental risk assessments, or residue study data to justify any proposed withdrawal period(s). | |
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| IV.5.3. | The specific rules set out in Part IV.5.3.1 to IV.5.3.12 shall apply in order to demonstrate well-established veterinary use. | |
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| IV.5.3.1. | In order to establish a well-established veterinary medicinal use of constituents of veterinary medicinal products, the following factors shall be taken into account: (a) the time over which an active substance has been regularly used in the target species using the proposed route of administration and dosage regimen; (b) quantitative aspects of the use of the active substance(s), taking into account the extent to which the substance(s) has or have been used in practice, and the extent of use on a geographical basis; (c) the degree of scientific interest in the use of the active substance(s) (reflected in the published scientific literature); (d) the coherence of scientific assessments. | |
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| IV.5.3.2. | Different periods of time may be necessary for establishing well-established use of different active substances. In any case, the period of time required for establishing a well-established veterinary use of a constituent of a medicinal product shall not be less than 10 years from the first systematic and documented use of that substance as a veterinary medicinal product in the Union. | |
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| IV.5.3.3. | Veterinary use does not exclusively mean use as an authorised veterinary medicinal product. Well-established veterinary use refers to the use for a specific therapeutic purpose in the target species. | |
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| IV.5.3.4. | If a substance in well-established use is proposed for entirely new therapeutic indications, it is not possible to solely refer to a well-established veterinary use. Additional data on the new therapeutic indication, together with appropriate safety and residue tests and preclinical and clinical data shall be provided and, in such a case, applications based on Article 21 is not possible. | |
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| IV.5.3.5. | The published documentation submitted by the applicant shall be freely available to the public and published by a reputable source, preferably peer-reviewed. | |
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| IV.5.3.6. | The documentation shall contain sufficient details to allow an independent assessment. | |
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| IV.5.3.7. | The documentation shall cover all aspects of the safety and/or efficacy assessment of the product for the proposed indication in the target species using the proposed route of administration and dosage regimen. It shall include or refer to a review of the relevant literature, taking into account pre- and post-marketing studies and published scientific literature concerning experience in the form of epidemiological studies and, in particular, of comparative epidemiological studies. | |
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| IV.5.3.8. | All documentation, both favourable and unfavourable, shall be communicated. With respect to the provisions on well-established veterinary use, it is in particular necessary to clarify that bibliographic reference to other sources of evidence (post-marketing studies, epidemiological studies etc.) and not just data related to tests and trials may serve as a valid proof of safety and efficacy of a product if the applicant explains and justifies the use of those sources of evidence satisfactorily. | |
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| IV.5.3.9. | Public assessment reports or freedom of information summaries cannot be considered to supply sufficient information, apart from the assessment report published by the Agency following the evaluation of an application for the establishment of maximum residue limits, which may be used in an appropriate manner as literature, particularly for the safety tests. | |
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| IV.5.3.10. | Particular attention shall be paid to any missing information, and justification shall be given as to why demonstration of an acceptable level of safety and/or efficacy may be supported although some information is lacking. | |
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| IV.5.3.11. | The critical expert reports regarding safety and efficacy shall explain the relevance of any data submitted, which concern a product different from the product intended for marketing. A judgement shall be made whether or not the product studied in the bibliography may be satisfactorily or scientifically bridged to the product, for which the application for a marketing authorisation has been made in spite of the existing differences. | |
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| IV.5.3.12. | Post-marketing experience with other products containing the same constituents is of particular importance and applicants shall put a special emphasis on this issue. |
IV.6. Applications for limited markets
| IV.6.1. | A marketing authorisation may be granted for a limited market in the absence of comprehensive safety and/or efficacy data when, as provided for in Article 23, the applicant demonstrates that the product is intended for use in a limited market and that the benefit of availability of the new product outweighs the risk associated with the omission of some of the safety or efficacy data required by this Annex. | |
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| IV.6.2. | For such applications, the applicant shall submit Parts 1 and 2 as described in this Annex. | |
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| IV.6.3. | For Parts 3 and 4, some of the safety or efficacy data required by this Annex may be omitted. As regards the extent of safety and efficacy data that may be omitted, the relevant guidance published by the Agency shall be taken into account. |
IV.7. Applications in exceptional circumstances
| IV.7.1. | In exceptional circumstances related to animal or public health, a marketing authorisation may be granted under Article 25 for a veterinary medicinal product, subject to certain specific obligations, conditions and/or restrictions. | |
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| IV.7.2. | For such applications, the applicant shall submit Part 1 as described in this Annex, together with a justification as to why the benefit of the immediate availability on the market of the veterinary medicinal product concerned outweighs the risk inherent in the fact that certain quality, safety or efficacy documentation has not been provided. | |
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| IV.7.3. | For Parts 2, 3 and 4, certain quality, safety or efficacy data required by this Annex may be omitted, if the applicant justifies that those data cannot be provided at the time of submission. For the identification of the essential requirements for all such applications, the relevant guidance published by the Agency shall be taken into account. | |
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| IV.7.4. | Post-authorisation studies may be requested as part of the conditions for marketing authorisation, and shall be designed, conducted, analysed and presented according to the general principles for quality, safety and efficacy tests set out in this Annex, and relevant guidance documents, as applicable depending on the issue to be addressed in the study. |
SECTION V
REQUIREMENTS FOR MARKETING AUTHORISATION APPLICATIONS FOR PARTICULAR VETERINARY MEDICINAL PRODUCTS
This Section lays down specific requirements for identified veterinary medicinal products related to the nature of the active substances contained therein.
V.1. Novel therapies veterinary medicinal products
V.1.1 General requirements
| V.1.1.1. | Depending on the active substance and the mode of action, a novel therapy veterinary medicinal product could fall under any of the three product categories: (a) veterinary medicinal products other than biological veterinary medicinal products; (b) biological veterinary medicinal products other than immunological veterinary medicinal products; (c) immunological veterinary medicinal products. | |
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| V.1.1.2. | In general, marketing authorisation applications for novel therapy veterinary medicinal products, as defined in Article 4(43), shall follow the format and data requirements described in Section II or III of this Annex depending on how the novel therapy is categorised. A full dossier containing Parts 1, 2, 3 and 4 shall normally be provided in accordance with the requirements described in Section II or III and any relevant guidance published by the Agency. Deviations from the requirements of this Annex may be possible when justified. Where appropriate and taking into account the specificities of novel therapy products, additional requirements may be relevant for particular types of products. | |
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| V.1.1.3. | The manufacturing processes for novel therapy veterinary medicinal products shall comply with the principles of Good Manufacturing Practice (GMP) adapted where necessary, to reflect the specific nature of those products. Guidelines specific to novel therapy veterinary products shall be drawn up, to properly reflect the particular nature of their manufacturing process. | |
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| V.1.1.4. | According to the specific nature of a novel therapy product the use of the product may potentially be associated with specific risks. Those risks shall be identified applying a risk profiling methodology to identify the risks inherent to the specific product and the risk factors contributing to those risks. In this context, risks would be any potential unfavourable effects that may be attributed to the use of the novel therapy product which are of concern to the target population and/or the user, the consumer, and/or the environment. The risk analysis may cover the entire development. Risk factors that may be considered include the origin of the starting material (cells etc.), the mode of action in the animal (proliferation, initiation of an immune response, permanence in the body, etc.), the level of cell manipulation (for example, the manufacturing process), the combination of the active substance with bioactive molecules or structural materials, the extent of replication competence of viruses or micro-organisms used in vivo, the level of integration of nucleic acids sequences or genes into the genome, the long-time functionality, the risk of oncogenicity, the off-target effects and the mode of administration or use. | |
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| V.1.1.5. | Based on the evaluation of the information on the identified risks and risk factors a specific profile of each individual risk associated with a specific product shall be established and may be used to determine and justify how the data set provided gives the necessary assurances for quality, safety and efficacy and is adequate to support a marketing authorisation application, especially for those aspects of novel therapy products that are beyond current knowledge. | |
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| V.1.1.6. | To address data gaps or uncertainties at the time of product authorisation, implementation of post-authorisation measures or studies may be considered on a case-by-case basis. In order to detect early or delayed signals of adverse reactions, to prevent clinical consequences of such reactions and to ensure timely treatment and to gain information on the long-term safety and efficacy of novel therapy veterinary medicinal products a risk management plan shall detail the measures envisaged to ensure such follow up. | |
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| V.1.1.7. | For any novel therapy product, in particular those considered as a nascent field in veterinary medicine, it is recommended to seek the advice of the Agency in a timely manner before submission of the marketing authorisation dossier in order to classify the product, determine the applicable dossier structure and to receive relevant information about the additional data set which may be necessary to support quality, safety and efficacy. |
V.1.2. Quality requirements
| V.1.2.1. | In general, description of the composition, the manufacturing method, consistency of production, controls of starting materials, controls implemented during the manufacturing process, finished product testing including implementation of an activity test or a quantification of the active substance and stability data shall be submitted. | |
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| V.1.2.2. | The data requirements for manufacturing and testing for novel therapy veterinary medicinal products of biological origin and classified as a biological product or as an immunological product shall in general be in accordance with those for biological or immunological medicinal products (as described in Section III of this Annex) including the need for a relevant potency test. There may be cases where additional requirements are applicable, for example, cells and vector gene constructs. | |
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| V.1.2.3. | For novel therapy veterinary medicinal products constructed by chemical synthesis, data requirements as for veterinary medicinal products other than biological products (as described in Section II of this Annex) are generally applicable. There may be cases where additional requirements are applicable, for example, a relevant potency test. |
V.1.3. Safety requirements
| V.1.3.1. | Depending on the nature of the product and its intended use, further data to evaluate safety for the target animal, the user, the consumer or the environment could be relevant as determined by a risk analysis in each case. | |
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| V.1.3.2. | The requirements of Directive 2001/18/EC shall be taken into consideration when the treated animal itself could become a genetically modified organism. While Directive 2001/18/EC applies to finished products containing genetic modified organisms, it remains the best technical guide currently available for listing the necessary data. In particular, a main issue is the integration rate of DNA into germ cells (thus transmissible to offspring) or the potential transmission of the genetically modified cells to offspring. It shall also be noted that this problem is not completely the same when considering companion animals and food-producing animals (human consumption of products containing genetic modified organisms). | |
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| V.1.3.3. | For substances intended for integration into or editing of the genome, appropriate tests shall be performed to evaluate the risk of off-target modifications and/or insertional mutagenesis. |
V.1.4. Efficacy requirements
| V.1.4.1. | Efficacy data requirements differ primarily depending on the intended indications for use in the target species. Depending on the novel therapy product categorisation and the intended use in the target species, the efficacy requirements set out in Sections II or III may be applicable for a novel therapy veterinary medicinal product. | |
| --- | --- | --- |
| V.1.4.2. | The indications claimed shall be supported by appropriate data in the target species. |
V.1.5. Specific data requirements for particular types of novel therapy products
V.1.5.1. Principles
| V.1.5.1.1. | Taking into account the specificities of novel therapy products, specific requirements additional to the standard requirements for evaluation of quality, safety and efficacy may be appropriate. | |
| --- | --- | --- |
| V.1.5.1.2. | The following sections highlight specific requirements to be considered for particular type of novel therapy products. Those specific requirements established for a particular type of novel therapy product represent a non-exhaustive list of requirements that may need to be adapted to the specific product concerned on a case-by-case basis and based on a risk analysis. | |
| --- | --- | --- |
| V.1.5.1.3. | In all cases and especially for novel therapies that are considered nascent in the field of veterinary medicine, applicants will need to take into account the current state of veterinary medicinal knowledge and the scientific guidance published by the Agency and the Commission, consistent with Section I of this Annex. |
V.1.5.2. Gene therapy veterinary medicinal products
| V.1.5.2.1. | Gene therapy products are biological veterinary medicinal products that contain an active substance which contains or consists of a recombinant nucleic acid used in or administered to animals with a view to regulating, repairing, replacing, adding or deleting a genetic sequence. Their therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence they contain, or to the product of genetic expression of this sequence. | |
| --- | --- | --- |
| V.1.5.2.2. | In addition to the data requirements set out in Sections II or III the following requirements shall apply: (a) information shall be provided on all the starting materials used for the manufacture of the active substance, including the products necessary for the genetic modification of cells, as applicable, subsequent culture and preservation of the genetically modified cells, taking into consideration the possible absence of purification steps; (b) for products containing a microorganism or a virus, data on the genetic modification, sequence analysis, attenuation of virulence, tropism for specific tissues and cell types, cell cycle dependence of the microorganism or virus, pathogenicity and characteristics of the parental strain shall be provided; (c) process-related impurities and product-related impurities shall be described in the relevant sections of the dossier and in particular replication competent virus contaminants if the vector is designed to be replication incompetent; (d) for plasmids, quantification of the different plasmid forms shall be undertaken throughout the shelf life of the product; (e) for genetically modified cells, the characteristics of the cells before and after the genetic modification, as well as before and after any subsequent freezing/storage procedures, shall be tested. For genetically modified cells, in addition to the specific requirements for gene therapy medicinal products, the quality requirements for cell therapy medicinal products and tissue engineered products shall apply; (f) off-target insertions (leading, for example, to tumours/cancer, metabolic dysfunctions) and insertional mutagenesis and genotoxicity (insertion of genetic elements and the expression of DNA-modifying proteins as mediators of genotoxic side effects) in target species need to be considered; (g) germline transmission studies shall be provided, unless otherwise justified. |
V.1.5.3. Regenerative medicine, tissue engineering and cell therapy veterinary medicinal products
| V.1.5.3.1. | Regenerative medicines are considered to encompass a wide area of products and therapies with a general purpose of restoring functions. Those medicines include cell-based therapies in which tissue engineered products are included. | |
| --- | --- | --- |
| V.1.5.3.2. | Cell therapy veterinary medicinal products are biological veterinary medicinal products that contain or consist of cells or tissues that have been subject to substantial manipulation in either nature or function so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor. They are presented as having properties for, or are used in or administered to animals with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues or to regenerating, repairing or replacing a tissue. | |
| --- | --- | --- |
| V.1.5.3.3. | In addition to the data requirements set out in Sections II or III the following requirements shall apply: (a) summary information shall be provided on procurement and testing of the animal tissue and cells used as starting materials. If non-healthy cells or tissues are used as starting materials, their use shall be justified; (b) the potential variability introduced through the animal tissues and cells shall be addressed as part of the validation of the manufacturing process, characterisation of the active substance and the finished product, development of assays, setting of specifications and stability; (c) for the genetic modification of the cells, the technical requirements specified for gene therapy products shall apply; (d) relevant information shall be provided on the characterisation of the cell population or cell mixture in terms of identity, purity (for example, extraneous agents and cellular contaminants), viability, potency, karyology, tumourigenicity and suitability for the intended medicinal use. The genetic stability of the cells shall be demonstrated; (e) the impact and interactions of any components likely to interact (directly or as a result of degradation or metabolism) with the active substance shall be investigated; (f) where a three-dimensional structure is part of the intended function, the differentiation state, structural and functional organisation of the cells and, where applicable, the extracellular matrix generated shall be part of the characterisation for those cell-based products. |
V.1.5.4. Veterinary medicinal product specifically designed for phage therapy
| V.1.5.4.1. | Bacteriophages are viruses that depend on bacterial hosts for proliferation and act very specifically on certain bacterial strains. Phage therapy may be used, for example, as an alternative to antibiotics. Generally, bacteriophages consist of a genome, comprised of single or double stranded DNA or RNA, encapsulated by a protein capsid. Due to the diversity of the intended targets for treatment and the specificity of the bacteriophages, it will be necessary to choose the suitable bacteriophage strain against the disease-causing bacterial strain on a case-by-case basis for the individual outbreak of the disease. | |
| --- | --- | --- |
| V.1.5.4.2. | The quality and quantity of the bacteriophages to be used in the finished product are normally variable. Therefore, a fixed qualitative and quantitative composition of bacteriophages will not be the usual situation as the phages need to be adapted on an ongoing basis. Based on this a seed stock of bacteriophages strains need to be established and maintained (comparable with a multi-strain approach). | |
| --- | --- | --- |
| V.1.5.4.3. | Bacteriophages as well as host bacteria/master cell banks for manufacturing shall preferably be produced based on a master seed system. Confirmation shall be provided that the bacteriophage used is lytic. | |
| --- | --- | --- |
| V.1.5.4.4. | The absence of resistance gene(s) and the absence of genes coding for virulence factors shall be shown on all master seeds. | |
| --- | --- | --- |
| V.1.5.4.5. | The indication shall be for prophylactic, metaphylactic and/or therapeutic treatment of one or several specific infection(s) or infectious disease(s). Efficacy of treatment is linked to the lytic activity of phages that confers bactericidal activity on those bacteriophages with specificity for the bacterial strain concerned. | |
| --- | --- | --- |
| V.1.5.4.6. | For genetically modified phages, the genetic modification shall be described. |
V.1.5.5. Veterinary medicinal product issued from nanotechnologies
| V.1.5.5.1. | Nanotechnologies are seen primarily as a technology to generate carriers for chemically synthesised substances but may also be carriers for biological substances. The use of nanoparticles may be a way of controlling delivery of substances with low solubility or toxic compounds. | |
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| V.1.5.5.2. | “Nanotechnology” corresponds to the design, characterisation, and production of nanomaterials by controlling shape and size at the nanoscale (up to around 100 nm). | |
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| V.1.5.5.3. | “Nanoparticles” are considered to have two or more dimensions at the nanoscale. | |
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| V.1.5.5.4. | Within the veterinary field, nanoparticles for drug delivery system are relevant as “products issued from nanotechnologies”: nanoparticles are conjugated with substances in order to change the pharmacokinetic and/or pharmacodynamic properties. mRNA drugs are rather encapsulated in nanoparticle delivery systems. | |
| --- | --- | --- |
| V.1.5.5.5. | In addition to the quality data requirements set out in Sections II or III the following requirements shall apply: (a) size distribution of particles shall be determined; (b) a suitable in vitro test for their function and possible delivery capacity (if used as drug delivery system) shall be used. | |
| --- | --- | --- |
| V.1.5.5.6. | With regard to safety, the kind of hazards that are introduced by using nanoparticles for drug delivery may be beyond conventional hazards imposed by chemicals in classical delivery matrices. Therefore, the following aspects shall be considered with regard to safety: (a) The nanoparticles for drug delivery could influence the toxicity of the medicinal product. The toxicity of the active substance is pivotal to the product but the toxicity of the nanoparticle for drug delivery shall also be considered, as they may introduce specific risks (agglomerates, cytotoxicity), may convey impurities by adsorption, may generate toxic materials by degradation or solubilisation, or may be transferred through physiological barrier (haemato-encephalic, foeto-placental, cell and nuclear membranes, etc.). In this context: (i) when physiological barriers are crossed, the impact of nanoparticles for drug delivery shall be investigated on the corresponding organ(s); (ii) the impact of agglomerates shall be investigated in the different targeted organs, focusing in particular on the risk of embolism in the smaller blood vessels; (iii) safety issues of the nanoparticles for drug delivery may be linked to a cumulative effect, a degradation profile or persistence in the body with negative effects on the functions of the targeted organs; (iv) safety issues might also be perceived at the cell level. Cells might not always be able to eliminate the nanoparticles conveyed through the cell membrane, leading to cytotoxicity especially via the induction of an oxidative stress. The toxicological assays to be implemented shall be able to assess this cytotoxicity and the related aspects, such as the generation of toxic free radicals and biopersistence. (b) The toxicology profile of the active substances contained in nanoparticles for drug delivery may differ as they may be distributed differently into various internal organs (different solubility in biological matrices), or as they may unexpectedly cross various biological barriers within the body, such as the brain barrier. (c) The side effects linked to the active substances may be exacerbated when they are delivered by nanoparticles. (d) Immunosafety issues such as immunotoxicity (direct damage to immune cells), immunostimulation, immunosuppression and immunomodulation (such as complement activation, inflammation, activation of the innate or adaptive immunity), were already identified for nanomedicines. (e) The capacity of nanoparticles to create inflammatory or allergic reactions shall be considered. The capacity to penetrate into the blood stream and to induce inflammatory reactions may lead to disseminated intravascular coagulation or fibrinolysis with further consequences such as thrombosis. The haemocompatibility of the nanoparticles shall therefore be checked. |
V.1.5.6. RNA antisense therapy and RNA interference therapy products
| V.1.5.6.1. | Antisense therapy and interference therapy products may be generated by synthesis or through recombinant techniques. | |
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| V.1.5.6.2. | Antisense RNA is a single stranded RNA that is complementary to a protein coding messenger RNA with which it hybridises, and thereby blocks its translation into protein. | |
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| V.1.5.6.3. | RNA interference is a biological process in which RNA molecules inhibit gene expression or translation, by neutralising targeted mRNA molecules. | |
| --- | --- | --- |
| V.1.5.6.4. | In addition to the data requirements set out in Sections II or III the following requirements shall apply: (a) the minimum amount of RNA segments per volume needs to be established as part of control tests of the finished product, as well as the confirmation that the RNA segments present the correct sequence; (b) for certain antisense therapy products falling under Section II of this Annex a potency bioassay may be needed for their release testing; (c) stability studies shall include a test to monitor the degradation rate of the RNA segments over time; (d) for RNA antisense therapy products, the possible harmful effects due to on- or off-target binding shall be addressed as well as possible non-antisense harmful effects due to, for example, accumulation, pro-inflammatory responses and aptamer binding; (e) for RNAi therapy products, the possible harmful effects of off-target interference (due to the positive RNAi strand) shall be addressed, as well as the possibility of crossing the blood-brain barrier and causing central nervous system disorders; (f) for RNA antisense therapy and RNA interference therapy products intended for gene therapy the requirements for gene therapy veterinary medicinal product shall be considered. |
V.2. Vaccine Antigen Master File
For particular immunological veterinary medicinal products and by derogation from Section IIIb, Part 2, the concept of a Vaccine Antigen Master File is introduced.
| V.2.1. | Principles | |
| --- | --- | --- |
| V.2.1.1. | For the purpose of this Annex, a Vaccine Antigen Master File means a stand-alone part of the marketing authorisation application dossier for a vaccine, which contains all relevant information on quality concerning each of the active substances, which are part of the veterinary medicinal product. The stand-alone part may be common to one or more monovalent and/or combined vaccines presented by the same applicant or marketing authorisation holder. | |
| --- | --- | --- |
| V.2.1.2. | The use of Vaccine Antigen Master Files is optional. For combined vaccines, the vaccine antigen(s) to be included in Vaccine Antigen Master File(s) shall be specified and a separate Vaccine Antigen Master File shall be required for each of them. | |
| --- | --- | --- |
| V.2.1.3. | The submission and approval of a Vaccine Antigen Master File shall comply with the relevant guidance published by the Agency. | |
| --- | --- | --- |
| V.2.2. | Content The Vaccine Antigen Master File dossier shall contain the information in Parts V.2.2.1 to V.2.3.3 extracted from the relevant sections of Part 1 (Summary of the dossier) and Part 2 (Quality documentation) as set out in Section IIIb of this Annex: | |
| --- | --- | --- |
| V.2.2.1. | Summary of the dossier (Part 1) The name and address of the manufacturer(s) and the site(s) involved in the different stages of manufacture and control of the active substance, accompanied by copies of the corresponding manufacturing authorisations, shall be given. | |
| --- | --- | --- |
| V.2.2.2. | Qualitative and quantitative particulars of the constituents (Part 2.A) The complete and exact name of the active substance (for example, virus or bacteria strain, antigen) shall be provided, in the same way as mentioned in any finished product. Information on product development relevant to the active substance shall be provided. | |
| --- | --- | --- |
| V.2.2.3. | Description of the manufacturing method (Part 2.B) The description of the manufacturing method for the active substance shall be provided including validation of the key stages of production and justification, if relevant, of any intermediate storage proposed. For inactivated vaccines, data relevant to the inactivation of the active substance, including the validation of the inactivation process shall be provided. | |
| --- | --- | --- |
| V.2.2.4. | Production and control of starting materials (Part 2.C) | |
| --- | --- | --- |
| V.2.2.4.1. | The standard requirements described in Section IIIb.2C and relevant to the active substance shall apply. | |
| --- | --- | --- |
| V.2.2.4.2. | Information on the active substance (for example, virus/bacteria strain), the substrate/s (cells, culture medium) and all the raw materials (pharmacopoeia or non-pharmacopoeia, biological or non-biological) used in the production of the active substance shall be provided. | |
| --- | --- | --- |
| V.2.2.4.3. | The dossier shall include the specifications, information on the processes implemented and on the tests to be conducted for the quality control of all batches of starting materials and results for a batch for all components used. | |
| --- | --- | --- |
| V.2.2.4.4. | TSE and extraneous agents (EA) risk assessment shall be provided, where applicable. It is to be noted that the target species retained for the finished products making reference to the Vaccine Antigen Master File shall be considered for the TSE and EA risk assessment. Warnings or restrictions of use may be brought in at the Vaccine Antigen Master File level depending on the information presented, which may be mitigated during the risk analysis at the level of the finished product. | |
| --- | --- | --- |
| V.2.2.4.5. | If the active substance is obtained by recombinant techniques, all corresponding relevant data on the genetically modified virus/bacteria shall be provided. | |
| --- | --- | --- |
| V.2.2.5. | Control tests during the manufacturing process (Part 2.D) The standard requirements described in Section IIIb.2D shall apply for the in-process control tests carried out during the manufacture of the active substance, including validations of key control tests and, if relevant, any intermediate storage proposed (prior to blending). | |
| --- | --- | --- |
| V.2.2.6. | Batch-to-batch consistency (Part 2.F) The standard requirements described in Section IIIb.2F shall apply for the demonstration of consistency in the manufacture of the antigen. | |
| --- | --- | --- |
| V.2.2.7. | Stability (Part 2.G) The standard requirements described in Section IIIb.2G to demonstrate the stability of the antigen and, where relevant any intermediate storage, shall apply. | |
| --- | --- | --- |
| V.2.3. | Evaluation and certification | |
| --- | --- | --- |
| V.2.3.1. | For vaccines containing new vaccine antigen(s) where no Vaccine Antigen Master File already exists, the applicant shall submit to the Agency a full marketing authorisation application dossier including all the Vaccine Antigen Master Files corresponding to each single vaccine antigen for which the use of a Vaccine Antigen Master File is intended. A scientific and technical evaluation of each Vaccine Antigen Master File shall be carried out by the Agency. A positive evaluation shall result in a certificate of compliance with Union legislation for each Vaccine Antigen Master File, which shall be accompanied by the evaluation report. The certificate shall apply throughout the Union. | |
| --- | --- | --- |
| V.2.3.2. | Part V.2.3.1 shall also apply to every vaccine, which consists of a novel combination of vaccine antigens, irrespective of whether or not one or more of those vaccine antigens are part of vaccines already authorised in the Union. | |
| --- | --- | --- |
| V.2.3.3. | Changes to the content of a Vaccine Antigen Master File for a vaccine authorised in the Union shall be subject to a scientific and technical evaluation carried out by the Agency. In the case of a positive evaluation, the Agency shall issue a certificate of compliance with Union legislation for the Vaccine Antigen Master File. The certificate issued shall apply throughout the Union. |
V.3. Multi-strain dossier
| V.3.1. | For certain immunological veterinary medicinal products and by derogation from the provisions of Section IIIb, Part 2, the concept of the use of a multi-strain dossier is introduced. | |
| --- | --- | --- |
| V.3.2. | A multi-strain dossier means a single dossier containing the relevant data for a unique and thorough scientific assessment of the different options of strains/combinations of strains permitting the authorisation of inactivated vaccines against antigenically variable viruses or bacteria for which rapid or frequent change in the composition of vaccine formulations is needed to ensure efficacy with regard to the epidemiological situation in the field. According to the epidemiological situation where the vaccine is intended to be used, a number of strains could be selected from those included in the dossier to formulate a final product. | |
| --- | --- | --- |
| V.3.3. | Each multi-strain dossier is applicable only to one virus species, bacteria genus or vector for a given disease; mixtures of various viruses belonging to different families, genera, species or bacteria belonging to different families or genera cannot be approved in the context of a multi-strain dossier. | |
| --- | --- | --- |
| V.3.4. | For new applications to multi-strain dossier marketing authorisations where no authorised multi-strain vaccine already exists for a particular virus/bacterium/disease, eligibility for the multi-strain dossier approach shall be confirmed by the Agency before submission of the application. | |
| --- | --- | --- |
| V.3.5. | The submission of multi-strain dossiers shall comply with relevant guidance published by the Agency. |
V.4. Vaccine platform technology
| V.4.1. | Principles | |
| --- | --- | --- |
| V.4.1.1. | Vaccine platform technology is a collection of technologies that have in common the use of a “backbone” carrier or vector that is modified with a different antigen or set of antigens for each vaccine derived from the platform. This includes, but may not be limited to, protein-based platforms (virus-like particles), DNA vaccine platforms, mRNA based platforms, replicons (self-replicating RNA) and viral and bacterial vector vaccines. | |
| --- | --- | --- |
| V.4.1.2. | Applications for marketing authorisations of immunological veterinary medicinal products manufactured based on vaccine platform technologies are considered to be eligible for reduced data requirements. A full dossier is required for the first product from a manufacturer based on a particular platform technology for a particular target species. At the time of submission of the first (full) dossier based on the platform technology, the applicant may submit in parallel a “Platform Technology Master File” comprising all data relative to the platform for which there is reasonable scientific certainty that will remain unchanged regardless of the antigen(s)/gene(s) of interest added to the platform. The nature of the data to be included in the Platform Technology Master File will depend on the type of platform. | |
| --- | --- | --- |
| V.4.1.3. | Once a Platform Technology Master File is certified, the certificate may be used to fulfil the relevant data requirements in subsequent applications for marketing authorisations based on the same platform and intended for the same target species. |
V.4.2. Evaluation and certification
| V.4.2.1. | The submission of Platform Technology Master Files shall comply with relevant guidance published by the Agency. A scientific and technical evaluation of a Platform Technology Master File shall be carried out by the Agency. A positive evaluation shall result in a certificate of compliance with Union legislation for the Platform Technology Master File, which shall be accompanied by the evaluation report. The certificate shall apply throughout the Union. | |
| --- | --- | --- |
| V.4.2.2. | Changes to the content of a Platform Technology Master File for a vaccine authorised in the Union shall be subject to a scientific and technical evaluation carried out by the Agency. | |
| --- | --- | --- |
| V.4.2.3. | In the case of a positive evaluation the Agency shall issue a certificate of compliance with Union legislation for the Platform Technology Master File. |
V.5. Authorised homeopathic veterinary medicinal products
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