Abstract
BackgroundInitial studies of heartworm preventive drugs all yielded an observed efficacy of 100% with a single dose, and based on these data the US Food and Drug Administration (FDA) required all products to meet this standard for approval. Those initial studies, however, were based on just a few strains of parasites, and therefore were not representative of the full assortment of circulating biotypes. This issue has come to light in recent years, where it has become common for studies to yield less than 100% efficacy. This has changed the landscape for the testing of new products because heartworm efficacy studies lack the statistical power to conclude that finding zero worms is different from finding a few worms.MethodsTo address this issue, we developed a novel statistical model, based on a hierarchical modeling and parametric bootstrap approach that provides new insights to assess multiple sources of variability encountered in heartworm drug efficacy studies. Using the newly established metrics we performed both data simulations and analyzed actual experimental data.ResultsOur results suggest that an important source of modeling variability arises from variability in the parasite establishment rate between dogs; not accounting for this can overestimate the efficacy in more than 40% of cases. We provide strong evidence that ZoeMo-2012 and JYD-34, which both were established from the same source dog, have differing levels of susceptibility to moxidectin. In addition, we provide strong evidence that the differences in efficacy seen in two published studies using the MP3 strain were not due to randomness, and thus must be biological in nature.ConclusionOur results demonstrate how statistical modeling can improve the interpretation of data from heartworm efficacy studies by providing a means to identify the true efficacy range based on the observed data. Importantly, these new insights should help to inform regulators on how to move forward in establishing new statistically and scientifically valid requirements for efficacy in the registration of new heartworm preventative products. Furthermore, our results provide strong evidence that heartworm ‘strains’ can change their susceptibility phenotype over short periods of time, providing further evidence that a wide diversity of susceptibility phenotypes exists among naturally circulating biotypes of D. immitis.
Highlights
Initial studies of heartworm preventive drugs all yielded an observed efficacy of 100% with a single dose, and based on these data the US Food and Drug Administration (FDA) required all products to meet this standard for approval
It is possible that three doses are marginally more effective than two doses; these studies were insufficient in power to determine this. Based on these data and the results presented from the simulation (Table 2), it seems fairly obvious that in a given heartworm efficacy study, there is insufficient analytical power to say that one worm or zero worms in the treated group are different
Statistical issues related to efficacy Analysis of data to evaluate the treatment efficacy is challenging, especially when the number of animals involved in the study is small
Summary
Using the newly established metrics we performed both data simulations and analyzed actual experimental data
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