The research and development costs involved in taking a pharmaceutical and developing a new product that gains approval for specific purpose in a designated species are enormous. Companies involved in new drug development must prove product efficacy in addition to safety in order to gain approval from the relevant regulatory authorities. Approved product information is then summarised in the official Data Sheet or product insert, which must list contraindications, drug interactions and reported side effects in addition to the dosing information and specific indications. Even when a product licence has been gained, any new claim for that product's efficacy must be prior approved by the Veterinary Medicines Directorate, Food and Drug Administration or equivalent following successful application and completion of further studies, again requiring authorisation from the regulatory authorities. In the UK, such work requires an Animal Test Certificate. In Europe, where horses are classified as food-producing animals, the further complication is that the safety of the product in terms of maximum permitted meat residue limit and recommended withholding period must also be determined.
The advantages of prescribing a veterinary medicine licensed for a specific condition are that both animal and consumer safety should be maximised by reducing potential adverse effects and that some level of efficacy, by definition, has been established. The disadvantages of the licensing system are that licensed products will inevitably be more expensive, and that new product development for less common equine conditions is unlikely to occur due to prohibitive economic constraints. In Europe, the medicines ‘cascade’ was established as ‘best practice’ for prescription of medicines when a licensed product is not available in that species for the required condition. Following this algorithm, a product licensed for a different purpose in the target species should be prescribed, or failing that a product licensed in a different species. Only when no licensed animal product is available should a human medication be prescribed, and a minimum 6-month meat withdrawal time is then required.
Although the cascade system has its detractors, it aims to prevent the uncontrolled use of human medications by the veterinary profession, to preserve antibiotic efficacy and to reduce the likelihood of unacceptable drug residues entering the food chain. In Europe, food safety is dependent on both veterinary compliance with the cascade system of prescribing, and an accurate system of drug recording and animal identification. Certain drugs such as phenylbutazone may not be used at all in food-producing animals, as it has not been possible to establish maximum residue limits, and there are known risks of exposure to the drug in human consumers. The presence of phenylbutazone in UK horse carcasses has been estimated to be as high as 3% by the European Foods Safety Authority, with the main reason for this being illegal entry of horses to the food chain, rather than incorrect veterinary prescribing . In order to improve this situation the European Foods Safety Authority has recommended an improved, mandatory identification system to aid the traceability of horses and harmonisation of the phenylbutazone testing system between member states.
The article by Barton et al. in this issue of the Equine Veterinary Journal compares the efficacy of 2 preparations of firocoxib in horses – one specifically designed and licensed for horses, and the other a chewable tablet form, licensed for dogs . The authors suggest that the use of the dog formulation of firocoxib has become more common by veterinarians in the USA because it is less expensive than the equine formulation. The results of their investigations confirm that there is no difference in this case between the canine and equine formulations in terms of plasma concentrations reached and relative ex vivo efficacy. This raises a potential moral and ethical dilemma when choosing a treatment for a patient, particularly when the owner has limited financial resources and the medication concerned is required for analgesia in the animal under-our-care. However, medicines legislation is clear that the licensed preparation is the correct drug to prescribe in this situation.
In many ways a move away from phenylbutazone use in equids to a relatively cheap nonsteroidal anti-inflammatory that is an effective analgesic, with improved spectrum of cyclo-oxygenase inhibition would be beneficial. The reduced use of phenylbutazone would also lead to a reduced risk of its inadvertent entry into the food chain in horse carcasses via criminal activity, and would be favoured by the European Medicines Agency. Historical evaluation of the equine pharmaceutical market suggests that competition between manufacturers will eventually lead to the production of cheaper versions of the most commonly used drugs, such that cheaper licensed versions of firocoxib may be produced for equine use. However, use of unlicensed preparations by equine veterinary surgeons is not likely to have the same economic impact on future product development. Indeed, use of unlicensed medications is more likely to reduce the investment of pharmaceutical companies in new products, to the eventual detriment of both our patients and the veterinary profession.
Although the different firocoxib preparations discussed by Barton et al. in this issue were shown to have similar equine peak plasma concentration , it also should be remembered that compound formulation is of major importance in horses. Low bioavailability of many generic compounds occurs in horses due to the combined effects of the low gastric pH and the complex hindgut environment, rendering them useless. As an example, many attempts have been made to source cheaper versions of omeprazole for use in equine gastric ulceration, rather than the licensed product. Many generic formulations of omeprazole have been shown to be a waste of client money in this respect, as they are ineffective in raising gastric pH, usually due to poor bioavailability following oral dosing . Veterinarians should not assume that generic preparations are the equivalent to authorised and licensed veterinary medicines, unless detailed bioequivalence studies have been performed in the target species. Safety considerations also dictate that an unlicensed product is likely to present more risk to the health of an animal than the licensed version.
In cases where there is no licensed product in the horse or other animal species for a specific condition, then the UK Veterinary Medicines Directorate dictates that off-label unlicensed products may be used but only after explanation of risk to the owner. In order to comply with the UK law in such cases, veterinary surgeons must explain the risks and gain signed consent using an appropriate form. These should then be stored in order to demonstrate compliance with the regulations. As specific withdrawal times are unlikely to have been established for use of these products in horses, the horse must also either be excluded from the food chain by the owner, or the drug recorded in its passport with a recommended 6-month withdrawal time. Alternative procedures enabling the use of unlicensed products when clinical circumstances justify this exist in other countries.
When prescribing any medication, equine veterinarians should consider the likely range of side effects that may occur and discuss the potential for these with the owner. Off-label use of compounds such as dexamethasone, for example, should be accompanied by discussion of the occasional report of induced laminitis. Owners should be encouraged to report potential side effects or adverse reactions to their veterinary surgeons, and this should be followed by an appropriate professional response. In the case of genuine adverse reaction to a licensed medication, this should always be followed in the UK by completion of an Adverse Reaction form, and submission to the Veterinary Medicines Directorate. When adverse responses occur to unlicensed medications, it is more likely that the prescribing veterinary surgeon will be held accountable unless there has been clear informed consent from the client prior to the drug's administration.
The continued development of specific licensed drugs for equine use is ideal for the veterinary profession. With responsible use, market forces should dictate that these products become more widely available and economically viable to the majority of our clients. Unlicensed products should only be used in specific circumstances according to cascade regulations in Europe, and only after specific acceptance of risk by the client. While in some cases cheaper generic compounds may be available it must be remembered that cheaper is not always better, either for the economics of our clients or for the health of our patients.