Anthelmintic Equivalence

Certain anthelminthics, particularly the newer macrocyclic lactones, show a low correlation between plasma levels and efficacy. Therefore it is acceptable to undertake a clinical endpoint study to demonstrate bioequivalence, rather than the more accepted technique of comparative bioavailability studies. The VICH anthelminthic guidelines refer to ‘product equivalence’ and this is an acceptable approach to register a ‘similar’ product, by comparing efficacy with a reference product.

The question has arisen regarding the acceptability of comparing label claims between the ‘similar’ product and the reference product.

Comparative bioavailability studies tend to allow all the claims of the reference product to be transferred to the ‘similar’ product if bioavailability is proven, since the pharmacokinetic profiles of the two products are so similar. It is possible that effect equivalency (clinical endpoint) might be obtained by two products that have the same active, but the pharmacokinetic profiles are not as closely matched as those required to claim bioequivalence after comparative bioavailability studies.

The VICH Guideline on the Efficacy of Anthelminthics: General Requirements requires two dose confirmation studies, using the dose-limiting parasite (the least sensitive parasite to the anthelminthic) to prove product equivalence. (The dose-limiting parasite is defined as a parasite that will be identified during dose determination studies that will identify the dosage of the drug at which it shows 90% effectiveness. Any lower concentration of the product will show an effectiveness below 90% for the dose limiting parasite even though it will adequately treat other parasites [90% or better effectiveness] in the host.)

Because product equivalence is based on the least sensitive (dose-limiting) helminth species, if the product contains the same active as the reference product, then the same spectrum of activity of the reference product against other helminths can be extrapolated to the ‘similar’ product.

Should comparative bioavailability be unproven, and product equivalency be based on efficacy against helminths, then ectoparasite efficacy claims will need to be proven separately, and will not be extrapolated from reference product to ‘similar’ product on this basis.

Should it be proven, however, that the product is effective against the least sensitive ectoparasite species, then ectoparasite efficacy claims from the reference product may be extrapolated to the ‘similar’ product.

The ACVM Group has adopted the following policy to cover this situation:

“If product equivalence of anthelminthics is proven according to VICH guidelines of anthelminthic efficacy, then the helminth efficacy claims for the animal species which have been tested for the reference product may be extrapolated to the product for which equivalence is claimed (the ‘similar’ product). Ectoparasite efficacy claims will need to be proven separately, and no extrapolation will be allowed. Should it be proven, however, that the product is effective against the least sensitive ectoparasite species, then ectoparasite efficacy claims from the reference product may be extrapolated to the ‘similar’ product for the animal species tested”.