Thus, dose confirmation

studies need to be conducted in a location(s) and in such a manner that the chosen rationale(s) is supported by data and meets the requirements of the current guidelines for anthelmintics. At least one dose confirmation study must be conducted BI 2536 mouse with the final formulation to be commercialized and should include the dose-limiting parasite(s) for each anthelmintic used in the combination. The number, location, design and analysis of these studies should be based on existing guidelines for single-constituent active products (Section 6.2). To investigate efficacy against adult parasites, naturally infected animals are preferred and infections should include, where possible, known drug-resistant isolates or populations of nematodes; strains resistant to one or more of the anthelmintic constituent actives in the combination should be included if available.

The efficacy of each individual constituent Crizotinib chemical structure active in the combination should be verified against the presumed resistant isolates to validate the inclusion of data from these trials in the dossier (e.g., the resistant populations must be proven to be present). Efficacy against larval stages should be determined using experimental infections of nematodes from drug-resistant isolates (including, if available, isolates obtained within the previous 10 years) to permit claims on the product label. For such purposes, ‘resistance’ can attributed to a population of a parasite species that exhibits substantial reductions in efficacy (e.g., to ≤80%) when treated with a dose of the anthelmintic which is historically ≥95% efficacious against that species (based on adequate evidence from worm counts and/or FEC reductions) (Coles et al., 1992 and Anonymous, 2003). These isolates should encompass the extent of AR present in the country of interest

and should be agreed by the relevant regulatory agency as part of the preliminary discussions over the content of the dossier required for consideration nearly for approval. Efficacy against nematode species that can exist as hypobiotic larvae should be included in the studies if label claims for such parasites are sought. Analyses of parasite data in support of efficacy claims should be based on estimates of adult and larval stage worm counts as specified in the earlier guidelines (Section 6.2). Field efficacy studies shall be conducted using reduction in FEC (with supporting larval culture or PCR data) after treatment with the final formulation of the combination product to be commercialized to confirm efficacy and safety in the field in accordance with the current guidelines for single constituent active products (Wood et al., 1995, Anonymous, 1999a, Anonymous, 1999b, Anonymous, 2000a, Anonymous, 2000b, Anonymous, 2000c, Vercruysse et al., 2001 and Vercruysse et al., 2002).