This example also demonstrates consequences from failures to understand dosing in adequate detail (8, 36, 46). As we have discussed elsewhere, after CT successes with one dosing regimen, drugs can fail in subsequent CTs because investigators use inadequately tested alternative dosing (47). In the phase 2 study with tarenflurbil, the dose-response plots showed straight line slopes that continued to increase at the highest blood concentrations, an indication that the necessary or optimal dose may not have been reached. The dose used in the phase 3 study was drawn from within the dose range used in the phase 2 study, which was ineffective for the main outcome of cognitive changes. Therefore, a clinically effective tarenflurbil dose may not have been evaluated in phase 3, and so, this phase 3 trial does not provide a definitive test of the drug’s efficacy and postulated mechanism of therapeutic action (25, 47). Conflicting reports of tarenflurbil effects on Aβ42 in animal models (43–45) and failures to observe changes in Aβ42 in the cerebrospinal fluid (CSF) of normal elderly volunteers after 21 days of treatment (48)
