On the 10th of February 2009 the CVMP (Committee for Medicinal Products for Veterinary Use) started an European referral procedure for all strengths of water soluble powders and oral solutions containing doxycycline hyclate indicated for use in chicken and turkeys intended to be administered via drinking water.

All doxycycline products - oral solutions and products with and without an acid stabiliser - are treated as one and the same type of product. The matter was referred to the CVMP by the United Kingdom due to concerns that differences in the posology and indications of such products may present a potential serious risk to public and animal health.

All Marketing Authorisation Holders of one or more of the 172 EC doxycycline authorisations for chickens and/or turkeys have to substantiate the efficacy of their product(s) in relation to dosage and duration of medication and potential selection of antimicrobial resistance. The referral was triggered by generic applications for products containing doxycycline having different dosages and indications, whilst the dossiers of the originators contained very limited information. As it is no longer possible to question the efficacy of a generic application and it is also not possible to solely question the efficacy of the originator, a Member State not willing to accept a generic application can only initiate a class referral.

It is interesting to see that the focus of this referral is now limited to doxycycline and that the other tetracyclines are not in the scope of this referral. The UK recently refused to accept the indication for treatment of E.coli in chickens for doxycycline, but does have this indication for older class tetracyclines at similar dosages. It is well known that the pharmacokinetic properties of doxycycline are superior to those of for instance oxytetracycline and chlortetracycline. In order to obtain the same plasma concentrations these older generation tetracyclines have to be dosed approximately 3-5 times higher. Therefore if one questions efficacy of doxycycline - and is worried about under dosing in relation to development of resistance -, then why not include the whole group? It is not impossible and perhaps even logical that we will see more class referrals in the near future, including one for all tetracyclines. Obviously this is not something industry is looking forward to, as referrals are time consuming, require valuable resources - that could otherwise be used for new development - and do not bring any extra revenues. These class referrals will bring us closer to harmonisation of SPC's and may even result in some kind of monograph system, i.e. fixed dosages for fixed claims. Many of the older dossiers - authorised 10 to 20 years ago - will contain limited information, which will not be in line with the present requirements for demonstration of efficacy. However, it is also clear that some companies may have heavily invested in specific claims and will not be happy to share this confidential information with other companies.

This class referral for doxycycline involves more products and marketing authorisation holders than any of the previous referrals. It will be interesting to see what the outcome will be and how CVMP will deal with "confidential" information submitted by individual companies. What will happen with products having no substantial clinical information? And how to deal with withdrawal periods of individual products - in absence of new residues studies -, should the required fixed dosages be increased beyond those presently authorised? Will the CVMP require applicants to submit an updated environmental risk assessment should the dosages be increased? Finally, is it realistic to assume that all products containing doxycycline - oral solutions and products with and without an acid stabiliser - have identical pharmacokinetic profiles? It is clear that many questions remain and that this class referral will set a precedent for others to come …….