MARKET AUTHORISATION

2. MARKET AUTHORISATION

2.1. Feed additives

After the Swann report (1969), the Directive 70/524 concerning additives in feeding-stuffs (Table 1) defined the marketing authorisation rules at the European level for all the member states. In the late 1990s, the use of several compounds such as avoparcin (01/04/97), ardacin (01/04/98), virginiamycin, tylosin phosphate, spiramycin, and bacitracin zinc (01/07/99) were suspended by the European commission. At the time of writing, authorised growth pro- moters are flavophospholipol, sodium monensin, salinomycin, and avilamycin, and the European commission proposed to stop their usage in 2006.

European regulations about feed additives define the level of incorporation in feed and the period of usage in animals. The presence of additives in feed is labelled. The use of additives in feed differ between animal species and depends on the type of production. It is routinely used in different kinds of industrial production in Europe and excluded from others according to technical require- ments. Some drugs used for their coccidiostatic effect have an antimicrobial effect, mainly on Gram-positive bacteria, such as ionophores. The Commission Directive 2001/79/EC fixes guidelines for the assessment of additives in animal nutrition. In the preamble of the directive, it is recognised that the increasing

Table 1. European regulations and guidelines for antimicrobials marketing authorisation Veterinary medicine

Feed additives

European Council Directive 81/851/EEC of 28 September 1981 on the Council Directive 70/524/EEC of 23 November 1970 regulations

approximation of the laws of the member states relating concerning additives and feeding-stuffs. Official Journal to veterinary medicinal products. Official Journal

L270, 14/12/1970, p. 0001–0017 L317 of 6 Nov 1981

Council Directive 81/852/EECof 28 September 1981 on the Council Directive 96/51/EC of 23 July 1996 amending approximation of the laws of the member states relating to

Directive 70/524/EEC concerning additives in feedingstuffs analytical, pharmaco-toxicological, and clinical standards and

Official Journal L235, 17/09/1996, pp. 0039–0058 protocols in respect of the testing of veterinary medicinal products. Official Journal L317 of 6 November 1981, amended by Council Directive 87/20/EEC, 92/18/EEC, and 93/40/EEC

Council regulation 2377/90 Regulation (EEC) No. 2377/90 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. Official Journal L67 of 7/03/1997.

Guidelines EMEA/CVMP/627/01—Guideline for the demonstration of Commission Directive 2001/79/EC of 17 September 2001 efficacy for veterinary medicinal products containing

amending Council Directive 87/153/EEC fixing antimicrobial substances.

guidelines for the assessment of additives in animal nutrition. Official Journal of the European Communities

EMEA/CVMP/244/01—Guideline on pre-authorisation studies

2001, 6/10/2001m L267/1–25.

to assess the potential for resistance resulting from the use of

P ascal Sander

antimicrobial veterinary medicinal products. EMEA/CVMP/234/01—Revised guideline on safety evaluation of antimicrobial substances regarding the effects on

human gut flora.

Antibiotic Use in Animals 653 prevalence of antibiotic-resistant bacteria is of major concern to public health

and that the resistance caused by the use of antibiotics as feed additives contributes to the overall levels of resistance. The guidelines for additives thus require the dossier to include assessments of (1) the risk of selection and/or transfer of antibiotic resistance, (2) the risk of any increased persistence and shedding of enteropathogens in order to ensure the safety of use of those addi- tives, (3) the risk for the consumer which could result from the consumption of food containing residues of the additive and of the environmental impact of feed additives. These guidelines amend previous guidelines established in the light of advances in scientific and technical knowledge. If the active substance has an antimicrobial activity at feed concentration level, the minimum inhibitory concentration (MIC) should be determined in appropriate patho- genic and non-pathogenic, endogenous, and exogenous bacteria. The ability of the additive to select cross-resistance to relevant antibiotics and to select resistant bacterial strains under field conditions in the target species has to

be studied by relevant tests. The effect of the additive has to be determined on a number of opportunistic pathogens present in the digestive tract (e.g., Enterobacteriaceae, Enterococci, and Clostridia) and on the shedding or excre- tion of relevant zoonotic microorganisms (e.g., Salmonella spp, Campylobacter spp.). Moreover, the directive 2001/79/EC encourages the development of field studies to monitor antimicrobial resistance and the data provided by these mon- itoring programmes are required in the evaluation dossier.

2.2. Veterinary drugs

The process of harmonisation of risk–benefit assessment for veterinary drugs began at the beginning of the 1980s (Table 1). Three evaluation proce- dures are defined: national, mutual recognition, and centralised for new innov- ative products. European guidelines are provided by the European Medicine Evaluation Agency (EMEA) and define the type of pre-clinical and clinical studies necessary to define therapeutical indications of an antimicrobial and the dosage regimen in the different animal species. On the basis of interna- tional recommendations, EMEA experts have reviewed the problem of devel- opment of antimicrobial resistance after veterinary usage and reinforced risk evaluation (Anonymous, 1999). Several guidelines have been modified to pro- vide new data about risk of selection of resistant bacteria during treatment and the mechanism of resistance and to promote the development of a dosage regimen based on the pharmacokinetic/pharmacodynamic approach for new products (Toutain et al., 2002).

For a new veterinary medicine, information is requested about the drug, its mechanism of action, the activity spectrum determined by MICs against a wide range of Gram-negative and Gram-positive bacteria including target

654 Pascal Sanders bacteria (Escherichia coli, Pasteurella multocida, Mannheima haemolytica,

Staphylococcus spp., Streptococcus spp., etc), zoonotic bacteria (Salmonella spp., Campylobacter spp.), and commensal bacteria (E. coli, Enterococci), and also bacteria representative of the human and animal intestine flora. This phar- macodynamic information is completed with the evaluation of cross-resistance, data on the mechanisms of resistance, their genetics, and the risk of spread. The pharmacokinetics of the drug in animals is described with particular insight on the distribution in the intestinal lumen. To regularly re-evaluate the drug, the monitoring of antimicrobial resistance for veterinary pathogens tar- geted by the drug is requested from pharmaceutical companies which have to encourage and support monitoring programmes in member states.

The risk assessment of veterinary drugs residue was defined by the council regulation, 2377/90. The process makes it possible to determine maximum residue limits in tissue and animal products (milk, eggs, honey) before clinical trials in the European Union. The effect of antimicrobial residues on the human intestinal flora is evaluated by the definition of a microbiologically acceptable daily intake on the basis of in vitro or in vivo data. For compounds recently approved, the microbiological acceptable daily intake (ADI), defined on the basis of antimicrobial effect evaluation is, the basis for the maximum residue limit determination.