In short, first-in-human trials are typically launched on the basis of a pivotal laboratory study showing statistically significant differences between treatment and control arms. In addition to decrying the "p-value" fetish- in which researchers, journal editors, and granting agencies view "statistical significance" as having magical qualities- Lowenstein also urged preclinical researchers to test the "nuances" and "robustness" of their systems before moving into human studies.
He provided numerous provocative examples where a single preclinical study showed very impressive, "significant" effects on treating cancer in mice. When the identical intervention was tried with seemingly small variations (e.g. different mouse strains used, different gene promotors tried, etc.), the "significant effects" vanished. In short, Lowenstein's answer to the question of why so many human trials fail to recapitulate major effects seen in laboratory studies is: we aren't designing and reviewing preclinical studies properly. Anyone (is there one?) who has followed this blog knows: I completely agree. This is an ethical issue in scientific clothing. (photo credit: Rick Eh, 2008)