Meeting report: FDA public meeting on patient-focused drug development and medication adherence in solid organ transplant patients.

The Food and Drug Administration (FDA) held a public meeting and scientific workshop in September 2016 to obtain perspectives from solid organ transplant recipients, family caregivers, and other patient representatives. The morning sessions focused on the impact of organ transplantation on patients' daily lives and the spectrum of activities undertaken to maintain grafts. Participants described the physical, emotional, and social impacts of their transplant on daily life. They also discussed their posttransplant treatment regimens, including the most burdensome side effects and their hopes for future treatment. The afternoon scientific session consisted of presentations on prevalence and risk factors for medication nonadherence after transplantation in adults and children, and interventions to manage it. As new modalities of Immunosuppressive Drug Therapy are being developed, the patient perceptions and input must play larger roles if organ transplantation is to be truly successful.

Qualification of biomarkers for drug development in organ transplantation.

The drug development process is dependent upon having established end points for measuring drug efficacy and adverse effects. New drug development in organ transplantation suffers from having end points which are either outdated or which do not serve the purpose of addressing the current critical drug therapy problems. Numerous biomarkers have been examined in organ transplantation, but almost all would be classified as exploratory for drug development purposes. Some of the possible pathways out of this dilemma include investigator- or consortium-initiated research that would qualify the biomarkers as either probable or known valid biomarkers, help in identification of new end points in transplantation and their associated biomarkers, co-development of a new biomarker and drug for transplantation and the use of new clinical trial design methods which facilitate enriched or stratified transplant patient populations. With new biomarkers and new study design methodologies for drug development, improvement in the drug development process for transplantation is a real possibility that the transplant clinical and research community can help to bring about.

Summary of 2017 FDA Public Workshop: Antibody-mediated Rejection in Kidney Transplantation.

Despite major advances in understanding the pathophysiology of antibody-mediated rejection (AMR); prevention, diagnosis and treatment remain unmet medical needs. It appears that early T cell-mediated rejection, de novo donor-specific antibody (dnDSA) formation and AMR result from patient or physician initiated suboptimal immunosuppression, and represent landmarks in an ongoing process rather than separate events. On April 12 and 13, 2017, the Food and Drug Administration sponsored a public workshop on AMR in kidney transplantation to discuss new advances, importance of immunosuppressive medication nonadherence in dnDSA formation, associations between AMR, cellular rejection, changes in glomerular filtration rate, and challenges of clinical trial design for the prevention and treatment of AMR. Key messages from the workshop are included in this summary. Distinction between type 1 (due to preexisting DSA) and type 2 (due to dnDSA) phenotypes of AMR needs to be considered in patient management and clinical trial design. Standardization and more widespread adoption of routine posttransplant DSA monitoring may permit timely diagnosis and understanding of the natural course of type 2 and chronic AMR. Clinical trial design, especially as related to type 2 and chronic AMR, has specific challenges, including the high prevalence of nonadherence in the population at risk, indolent nature of the process until the appearance of graft dysfunction, and the absence of accepted surrogate endpoints. Other challenges include sample size and study duration, which could be mitigated by enrichment strategies.

Biomarkers and surrogate endpoints in renal transplantation: present status and considerations for clinical trial design.

Of major importance in clinical trials is the ability to predict individual patient outcome or endpoints using biomarkers, also known as variables or predictors, in as safe, efficient, and accurate a manner as possible. This review addresses the concepts and possible strategies for use of predictor and surrogate biomarkers in the design of clinical trials in renal transplantation. The statistical concepts apply equally well to other organ grafts.