Commission Regulation (EC) No 429/2008Dangos y teitl llawn

4. SECTION IV: STUDIES CONCERNING THE EFFICACY OF THE ADDITIVE

Studies shall demonstrate the efficacy for each proposed use and satisfy at least one of the characteristics set out in Article 5(3) of Regulation (EC) No 1831/2003, according to the categories and functional groups of feed additives as provided by Article 6 and Annex I of the said Regulation. Moreover such studies must permit the evaluation of the efficacy of the additive according to common farming practices in the EU.

The experimental design used must be justified according to the additive use, animal species and category. When using animals, the trials shall be conducted such that their health and husbandry conditions do not adversely affect the interpretation of the results. The positive and negative effects, both technological and biological, shall be described for each experiment. Absence of effects that impair the distinctive features of animal products shall also be demonstrated. Trials shall ideally be compliant with the criteria established by a recognised, externally-audited, quality assurance scheme. In the absence of such a scheme, evidence shall be provided to show that the work was done by qualified personnel using appropriate facilities and equipment and responsible to a named study director.

The trial protocol shall be carefully drawn up by the study director with regard to general descriptive data, for example methods, apparatus and materials used, details of the species, breed or strain of the animals, their number and the conditions under which they were housed and fed. For all studies involving animals, the experimental conditions shall be described according to 3.1.1.3. Final reports, raw data, study plans and well characterised and identified test substances shall be archived for future reference.

Studies shall be designed to demonstrate the efficacy of the lowest recommended dose of additive by targeting sensitive parameters in comparison to a negative and, optionally, a positive control group. Such studies shall also include the maximum recommended dose, where this is proposed. No single design is recommended, flexibility being provided to allow for scientific discretion in the design and conduct of the studies.

Attention shall also be paid to known or potential biological or chemical interactions between the additive, other additives and/or veterinary medicines and/or components of the diet, where this is relevant to the efficacy of the additive concerned (e.g. compatibility of microbial additive with coccidiostats and histomonostats or organic acid).

4.1. In vitro studies

For all technological and some sensory additives affecting the characteristics of feed, efficacy shall be demonstrated using a laboratory-based study. The study shall be designed to cover a representative range of materials to which the additive will be applied. Results shall be evaluated preferably by parameter-free tests, and shall demonstrate expected changes with a probability of P ≤ 0,05.

In vitro studies, particularly those which simulate aspects of the gastrointestinal tract, may be used for other types of additives in order to support the efficacy. These studies should be capable of statistical evaluation.

4.2. Short term efficacy studies with animals

Bioavailability studies may be used to demonstrate the extent to which a novel form or source of a nutrient or colorant can substitute for an equivalent additive already approved or established.

Digestion/balance studies may be used in support of animal performance studies to provide evidence of mode of action. In some cases, particularly in relation to environmental benefits, efficacy may be better demonstrated by balance studies and may be used in preference to long term efficacy studies. Such experiments shall use numbers and species/categories of animals appropriate to the conditions of use proposed.

Other short term efficacy studies with animals may be proposed as appropriate, and these may substitute for long term efficacy studies with animals, provided that this is fully justified.

4.3. Long term efficacy studies with animals

The studies should be carried out at least at two different locations.

The experimental design used must include consideration of adequate statistical power and Type 1 and 2 risks. The protocol must be sufficiently sensitive to detect any effects from the additive at the lowest recommended dose (Type 1 α risk, P ≤ 0,05 in general and P ≤ 0,1 for ruminants, minor species, pets and non-food producing animals) and of sufficient statistical power to guarantee that the experimental protocol meets the study objective. The Type 2 β risk shall be lower than or equal to 20 % in general, and 25 % for experiments with ruminants, minor species, pets and non-food producing animals, hence a power (1-β) greater than or equal to 80 % (75 % for ruminants, minor species, pets and non food producing animals).

It is recognised that the nature of some additives make it difficult to define experimental conditions under which optimal results may be achieved. Consequently, the possibility of using meta-analysis shall be considered when the number of trials available is greater than three. For this reason, similar protocol designs shall be used for all trials so that data can eventually be tested for homogeneity and pooled (if tests so indicate) for statistical evaluation at a level of P ≤ 0,05.

4.4. Duration of long term efficacy studies with target animals

Generally, the duration of efficacy trials shall correspond to the application period claimed.

Efficacy trials shall be carried out according to farming practices in European Union and be of the minimum duration as stated by Annex IV.

If an additive is applied for a specific and shorter period than given by the animal category definition, it shall be administered according to the proposed conditions of use. However, the observation period shall not be shorter than 28 days and shall involve the relevant end-points (e.g., for sows for reproduction number of piglets born alive when considering the gestation period, or the number and weight of weaned piglets when considering the lactation period).

For other species or animal categories for which a minimum duration period of studies was not established in Annex IV, a period of administration shall be taken in to account, according to the proposed conditions of use.

4.5. Efficacy requirements for additive categories and functional groups

For all additives intended to have an effect on animals, in vivo studies are requested.

For the categories of zootechnical additives and coccidiostats and histomonostats, efficacy shall be demonstrated by at least three long term efficacy studies. However, for some zootechnical additives and the other additive categories having an effect on animals, short term efficacy studies may be accepted if efficacy can be unequivocally demonstrated.

For other additive categories without a direct effect on animals at least one in vitro efficacy study shall be provided.

4.6. Studies on the quality of animal products where this is not the effect claimed

In order to demonstrate that the additive does not have a negative effect or other effect not requested on the organoleptic and nutritional (hygienic and technological if appropriate) characteristics of food deriving from animals fed with the additive (when this is not the effect desired), appropriate samples shall be taken during one of the efficacy trials. Two groups shall be observed: an unsupplemented group; and a group with the highest dosage proposed for the additive. The data shall allow statistical evaluation. Omission of these studies shall be adequately justified.