Draft Guideline Released by EMA on Pharmacological ADIs for Veterinary Medicinal Products

The European Medicines Agency (EMA) released a draft guideline on 23 January on pharmacological acceptable daily intake (ADI), titled Guideline on the approach to establish a pharmacological ADI. The guideline advises when to establish a pharmacological ADI, how to conduct studies and what endpoints must be addressed.

EU legislation requires that any food produced from animals that are treated with veterinary medicinal products be free from medicinal residue, metabolites or pharmacologically active substances. The legislation therefore mandates that Maximum Residue Limits (MRLs) be established for all pharmacologically active substances in the veterinary medicinal product used to treat the food-producing animal.

These MRL's are established using acceptable daily intakes based on toxicological or microbiological studies. If the substances exert pharmacological effects in humans at levels undetectable by toxicological or microbiological studies, the No Observed Adverse Event Level (NOAEL) should be used instead.

The guideline notes that "[a] pharmacological ADI needs to be established when pharmacological effects resulting from residues in animal products can be expected at doses in the same range or lower than toxicological effects."

Pharmacological ADI studies are not needed, however, if residues are not bioavailable in humans via the route of food consumption, if the only pharmacological activity is antimicrobial, if scientific evidence confirms that residues are devoid of pharmacological activity in humans, if the mode of action is irrelevant to humans, or if the toxicological ADI already covers the pharmacological endpoint.

The guideline further notes that many substances used in veterinary applications have a history of use in humans, and should therefore have data available. If no data is available, animal or in vitro studies may be conducted. Appropriate endpoints should be used based on the active compound's mode of action.

Data gathered from the studies should support the establishment of a residue threshold such as a Benchmark Dose (BMDL) or a NOAEL.

Comments on the draft guideline will be accepted until 31 July 2012.

• EMA - Guideline on the approach to establish a pharmacological ADI