Novel "SMARTer" Clinical Trial Design Improves Odds of Approval and Can Reduce Study Size By Over 80%: Modeling Use of a ctDNA "Optimizing Diagnostic" for Early Therapy Switching in Immuno-Oncology Trials.

Novel pivotal trial designs, that more clearly demonstrate increased benefit over Standard of Care (SOC), especially in oncology and immuno-oncology (IO), are presented. The benefit of therapy is maximized and sample size is dramatically reduced. The novel methodology includes the introduction of a biochemical "Optimizing Diagnostic", for example a cfDNA test that can detect poor response, when performed early after therapy is begun; this is used to change the therapy of the tested person early in the trial (typically to SOC), before clinical progression. Patients remain in "the new drug first" group, which is compared to SOC. An "Optimizing Diagnostic" is analogous to a "Companion Diagnostic"; both potentially allow approval of drugs that would otherwise fail. A companion diagnostic predicts benefit prior to therapy, the optimizing diagnostic (more accurately) predicts likelihood of benefit after initial therapy. Those patients deemed less likely to respond remain in the novel drug first arm, but are switched to SOC. A Sequential Multiple Assignment Randomized Trial" (SMART) design is proposed to evaluate if switching to SOC or SOC plus continuing the novel therapy is most beneficial. These designs will allow approval of therapy paths including novel agents when the novel agent could not be approved without this design. A good optimizing test may reduce the number of patients needed by 80%, dramatically reducing cost and time; more patients benefit and accrual is easier. Key PointsO_LIA new clinical trial design focused on testing a path that begins with a novel regimen (IO is featured) is presented. C_LIO_LIThe path includes an "optimizing diagnostic" that determines, early during treatment, if a patient should remain on the new regimen. C_LIO_LICompanion diagnostics define the path at a pre-treatment stage, optimizing diagnostics define the path early during treatment. Changes in therapy, typically to the SOC, is made based on the post-test probability of success. C_LIO_LIThe novel path is significantly more likely to lead to approval than the novel regimen alone. C_LIO_LIUse of the novel method can reduce the size of a trial by 80%, and allow approval of the path, when approval of the novel regimen, based on a head-to-head trial vs SOC, would not be possible. C_LI