The need for novel trial designs, master protocols, and research consortia in transplantation

Abstract

Large multicenter, randomized controlled trials are the paradigm for determining the efficacy and safety of new therapies. However, applying this classical approach to many areas of transplantation is difficult. For most types of organ transplants, the number of transplants performed is too small for such a trial (lung, pancreas, or vascular composite transplantation are examples). In larger populations such as kidney transplantation, the major unmet needs commonly involve small subsets of patients (antibody-mediated rejection, recurrent renal disease, etc). This issue is not unique to transplantation and has been successfully overcome in other areas of medicine.In oncology, for example, novel trial designs such as adaptive trial design and master protocols are now relatively common. In addition, the existence of multicenter, ongoing clinical research consortia have greatly enhanced the successful implementation of these novel trial designs. In this manuscript, we examine how novel trial designs, master protocols, and research consortia might enhance studies in transplantation aimed at the regulatory approval of new agents. Our premise is that more efficient approaches to clinical trials already exist and, through a coordinated effort by researchers, the pharmaceutical industry, and regulatory bodies like the FDA, they can be implemented in transplantation.

Estimating alloantibody levels in highly sensitized renal allograft candidates: Using serial dilutions to demonstrate a treatment effect in clinical trials

“…Changes in the antibody level should be apparent within 6 months after therapy at which time the cPRA can be easily measured and the effectiveness of a therapeutic agent determined. The “rapid” ability to evaluate effectiveness is beneficial to novel adaptive trial designs that are efficient for studying small patient populations with unique needs such as transplant candidates with 100% cPRA 21–23 . In the context of an adaptive trial design, patients could be initially treated with a single agent and if deemed effective (at least partially), another drug can be added and evaluated within the same trial.…”

Current Approaches to Desensitization in Solid Organ Transplantation

“…Resources and patients eligible to participate in these trials are finite. Novel adaptive trial designs can be utilized to efficiently study small heterogeneous populations with combination therapeutic regimens and address issues with suboptimal enrollment ( 56 ). Adaptive clinical trials adapt depending on predefined outcomes generally based on Bayesian probabilities.…”

What have we learned about how to prevent and treat antibody-mediated rejection in kidney transplantation?

“…The transplant community is a captive of our success, that is, excellent short‐term outcomes, with no new therapeutic drugs approved based on superiority of patient and graft survival since 1983, or BPAR since 1999 99 . Several groups are attempting to develop solutions to this conundrum through innovative trial design, biomarkers/surrogate endpoints, and the development of research consortia 3,4,100‐102 . Indeed, the Paris Transplant group and the Transplant Therapeutics Consortium, a public‐private partnership between the FDA, transplant community (eg, American Society of Transplantation and American Society of Transplant Surgeons), biopharmaceutical community, and the Critical Path Institute are actively validating an early (eg, 1 year) composite surrogate end point in kidney transplantation to allow for provisional drug approval and thereby encourage industry to invest in transplant clinical trials 100,101 .…”