The particulars and documents, which shall accompany applications for marketing authorisations pursuant to the third indent of Article 12(3)(j) shall be submitted in accordance with the requirements below.
Pre-clinical studies are required to establish the pharmacological activity and the tolerance of the product.
The pharmacodynamic effects of the active substance(s) included in the veterinary medicinal product shall be characterised.
First, the mechanism of action and the pharmacological effects on which the recommended application in practice is based shall be adequately described. The results shall be expressed in quantitative terms (using, for example, dose-effect curves, time-effect curves, etc.) and, wherever possible, in comparison with a substance the activity of which is well known. Where a higher efficacy is being claimed for an active substance, the difference shall be demonstrated and shown to be statistically significant.
Secondly, an overall pharmacological assessment of the active substance shall be provided, with special reference to the possibility of secondary pharmacological effects. In general, the effects on the main body functions shall be investigated.
Any effect of the other characteristics of the products (such as the route of administration or formulation) on the pharmacological activity of the active substance shall be investigated.
The investigations shall be intensified where the recommended dose approaches a dose likely to produce adverse reactions.
The experimental techniques, unless they are standard procedures, shall be described in such detail as to allow them to be reproduced, and the investigator shall establish their validity. The experimental results shall be set out clearly and, for certain types of tests, their statistical significance quoted.
Unless good reasons are given to the contrary, any quantitative modification of responses resulting from repeated administration of the substance shall also be investigated.
Fixed combinations may be prompted either on pharmacological grounds or by clinical indications. In the first case, the pharmacodynamic and/or pharmacokinetic studies shall demonstrate those interactions, which might make the combination itself of value in clinical use. In the second case, where scientific justification for the medicinal combination is sought through clinical experimentation, the investigation shall determine whether the effects expected from the combination can be demonstrated in animals and, at least, the importance of any adverse reactions shall be checked. If a combination includes a new active substance, the latter shall have been previously studied in depth.
Where relevant, data on the potential emergence of resistant organisms of clinical relevance are necessary for veterinary medicinal products. The mechanism of the development of such resistance is particularly important in this regard. Measures to limit resistance development from the intended use of the veterinary medicinal product shall be proposed by the applicant.
Where relevant, cross reference shall be made to data set out in Part 3.
Basic pharmacokinetic data concerning a new active substance are required in the context of assessment of the clinical safety and efficacy of the veterinary medicinal product.
The objectives of pharmacokinetic studies in the target animal species can be divided into three main areas:
descriptive pharmacokinetics leading to the determination of basic parameters;
use of these parameters to investigate the relationships between dosage regimen, plasma and tissue concentration over time and pharmacological, therapeutic or toxic effects;
where appropriate, to compare the kinetics between different target species and to explore possible species differences having an impact on target animal safety and efficacy of the veterinary medicinal product.
In the target animal species, pharmacokinetic studies are, as a rule, necessary as a complement to the pharmacodynamic studies to support the establishment of effective dosage regimens (route and site of administration, dose, dosing interval, number of administrations, etc.). Additional pharmacokinetic studies may be required to establish dosage regimens according to certain population variables.
Where pharmacokinetic studies have been submitted under Part 3 cross reference to such studies may be made.
In the case of new combinations of known substances which have been investigated in accordance with the provisions of this Directive, pharmacokinetic studies of the fixed combination are not required if it can be justified that the administration of the active substances as a fixed combination does not change their pharmacokinetic properties.
Appropriate bioavailability studies shall be undertaken to establish bioequivalence:
when comparing a reformulated veterinary medicinal product with the existing one,
where necessary for the comparison of a new method or route of administration with an established one.
The local and systemic tolerance of the veterinary medicinal product shall be investigated in the target animal species. The purpose of these studies is to characterise signs of intolerance and to establish an adequate margin of safety using the recommended route(s) of administration. This may be achieved by increasing the therapeutic dose and/or the duration of treatment. The report on the trials shall contain details of all expected pharmacological effects and all adverse reactions.
The purpose of clinical trials is to demonstrate or substantiate the effect of the veterinary medicinal product after administration at the proposed dosage regimen via the proposed route of administration and to specify its indications and contra-indications according to species, age, breed and sex, its directions for use as well as any adverse reactions which it may have.
Experimental data shall be confirmed by data obtained under normal field conditions.
Unless justified, clinical trials shall be carried out with control animals (controlled clinical trials). The efficacy results obtained should be compared with those from the target animal species that have received a veterinary medicinal product authorised in the Community for the same indications for use in the same target animal species, or a placebo or no treatment. All the results obtained, whether positive or negative, shall be reported.
Established statistical principles shall be used in protocol design, analysis and evaluation of clinical trials, unless justified.
In the case of a veterinary medicinal product intended primarily for use as a performance enhancer, particular attention shall be given to:
the yield of animal produce,
the quality of animal produce (organoleptic, nutritional, hygienic and technological qualities),
nutritional efficiency and growth of target animal species,
general health status of the target animal species.
All veterinary clinical trials shall be conducted in accordance with a detailed trial protocol.
Clinical field trials shall be conducted in accordance with established principles of good clinical practice, unless otherwise justified.
Before the commencement of any field trial, the informed consent of the owner of the animals to be used in the trial shall be obtained and documented. In particular, the animal owner shall be informed in writing of the consequences of participation in the trial for the subsequent disposal of treated animals or for the taking of foodstuffs from treated animals. A copy of this notification, countersigned and dated by the animal owner, shall be included in the trial documentation.
Unless the field trial is conducted with a blind design, the provisions of Articles 55, 56 and 57 shall apply by analogy to the labelling of formulations intended for use in veterinary field trials. In all cases, the words ‘for veterinary field trial use only’ shall appear prominently and indelibly upon the labelling.
The dossier on efficacy shall include all pre-clinical and clinical documentation and/or results of trials, whether favourable or unfavourable to the veterinary medicinal products, in order to enable an objective overall assessment of the risk/benefit balance of the product.
Wherever possible, particulars shall be given of the results of:
tests demonstrating pharmacological actions;
tests demonstrating the pharmacodynamic mechanisms underlying the therapeutic effect;
tests demonstrating the main pharmacokinetic profile;
tests demonstrating target animal safety;
tests investigating resistance.
Should unexpected results occur during the course of the tests, these should be detailed.
Additionally, the following particulars shall be provided in all pre-clinical studies:
a summary;
a detailed experimental protocol giving a description of the methods, apparatus and materials used, details such as species, age, weight, sex, number, breed or strain of animals, identification of animals, dose, route and schedule of administration;
a statistical analysis of the results, where relevant;
an objective discussion of the results obtained, leading to conclusions on the efficacy and safety of the veterinary medicinal product.
Total or partial omission of any of these data shall be justified.
All the particulars shall be supplied by each of the investigators on individual record sheets in the case of individual treatment and collective record sheets in the case of collective treatment.
The particulars supplied shall take the following form:
name, address, function and qualifications of investigator in charge;
place and date of treatment; name and address of owner of the animals;
details of the clinical trial protocol giving a description of the methods used, including methods of randomisation and blinding, details such as the route of administration, schedule of administration, the dose, identification of trial animals, species, breeds or strains, age, weight, sex, physiological status;
method of animal management and feeding, stating the composition of the feed and the nature and quantity of any feed additives;
case history (as full as possible), including occurrence and course of any intercurrent diseases;
diagnosis and means used to make it;
clinical signs, if possible according to conventional criteria;
precise identification of the formulation of the veterinary medicinal product used in the clinical trial and the physical and chemical test results for the relevant batch(es);
dosage of the veterinary medicinal product, method, route and frequency of administration and precautions, if any, taken during administration (duration of injection, etc.);
duration of treatment and period of subsequent observation;
all details concerning other veterinary medicinal products which have been administered during the period of examination, either prior to or concurrently with the test product and, in the latter case, details of any interactions observed;
all results of the clinical trials, fully describing the results based on the efficacy criteria and end points specified in the clinical trial protocol and including the results of the statistical analyses, if appropriate;
all particulars of any unintended event, whether harmful or not, and of any measures taken in consequence; the cause-and-effect relationship shall be investigated if possible;
effect on animals’ performance if appropriate;
effects on the quality of foodstuffs obtained from treated animals, particularly in the case of veterinary medicinal products intended for use as performance enhancers;
a conclusion on the safety and efficacy in each individual case or, summarised in terms of frequencies or other appropriate variables where specific mass treatment is concerned.
Omission of one or more items (a) to (p) shall be justified.
The marketing authorisation holder shall make all necessary arrangements to ensure that the original documents, which formed the basis of the data supplied, are kept for at least five years after the veterinary medicinal product is no longer authorised.
In respect of each clinical trial, the clinical observations shall be summarised in a synopsis of the trials and the results thereof, indicating in particular:
the number of control and test animals treated either individually or collectively, with a breakdown according to species, breed or strain, age and sex;
the number of animals withdrawn prematurely from the trials and the reasons for such withdrawal;
in the case of control animals, whether they have:
received no treatment,
received a placebo, or
received another veterinary medicinal product authorised in the Community for the same indication for use in the same target animal species, or
received the same active substance under investigation in a different formulation or by a different route;
the frequency of observed adverse reactions;
observations as to the effect on animal performance, if appropriate;
details concerning test animals which may be at increased risk owing to their age, their mode of rearing or feeding, or the purpose for which they are intended, or animals the physiological or pathological condition of which requires special consideration;
a statistical evaluation of the results.
Finally, the investigator shall draw general conclusions on the efficacy and safety of the veterinary medicinal product under the proposed conditions of use, and in particular any information relating to indications and contraindications, dosage and average duration of treatment and where, appropriate, any interactions observed with other veterinary medicinal products or feed additives as well as any special precautions to be taken during treatment and the clinical symptoms of overdosage, when observed.
In the case of fixed combination products, the investigator shall also draw conclusions concerning the safety and the efficacy of the product when compared with the separate administration of the active substances involved.
This Annex will be amended by the Commission in accordance with Articles 146 and 153. All references to Articles or to ‘this Directive’ in this Annex, unless otherwise specified, are to be understood as references to Directive 2001/82/EC.