Efficacy and Effectiveness Too Trials: Clinical Trial Designs to Generate Evidence on Efficacy and on Effectiveness in Wide Practice.

Efficacy trials, designed to gain regulatory marketing approval, evaluate drugs in optimally selected patients under advantageous conditions for relatively short time periods. Effectiveness trials, designed to evaluate use in usual practice, assess treatments among more typical patients in real-world conditions with longer follow-up periods. In "efficacy-to-effectiveness (E2E) trials," if the initial efficacy trial component is positive, the trial seamlessly transitions to an effectiveness trial component to efficiently yield both types of evidence. Yet more time could be saved by simultaneously addressing efficacy and effectiveness in an "efficacy and effectiveness too (EE2) trial." Additionally, hybrids of the E2E and EE2 approaches with differing degrees of overlap of the two components could allow flexibility for specific drug development needs. In planning EE2 trials, each stakeholder's current and future needs, incentives, and perspective must be considered. Although challenging, the ultimate benefits to stakeholders, the health system, and the public should justify this effort.

Identification of a B cell signature associated with renal transplant tolerance in humans.

Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.