A statistical approach for evaluating the effectiveness of heartworm preventive drugs: what does 100% efficacy really mean?

Background: 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. 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. Methods: To 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. Results: Our 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. Conclusion: Our 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.