Summary OF 2017 FDA Public Workshop: Antibody Mediated Rejection in Kidney Transplantation

AbstractBackgroundDespite 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 (TCMR), 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.MethodsOn April 12-13, 2017, the Food and Drug Administration (FDA) 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 GFR, and challenges of clinical trial design for the prevention and treatment of AMR.Results and ConclusionsKey messages from the workshop are summarized in Table 2. 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, have 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 (SEP). Other challenges include sample size and study duration, which could be mitigated by enrichment strategies. Background 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 (TCMR), 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. Methods On April 12-13, 2017, the Food and Drug Administration (FDA) 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 GFR, and challenges of clinical trial design for the prevention and treatment of AMR. Results and Conclusions Key messages from the workshop are summarized in Table 2. 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, have 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 (SEP). Other challenges include sample size and study duration, which could be mitigated by enrichment strategies. Corresponding author: Ergun Velidedeoglu, MD, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 6176, Silver Spring, MD 20993. Email: Ergun.Velidedeoglu@fda.hhs.gov Ergun Velidedeoglu, MD had primary responsibility in planning and organizing the workshop including the preparation of the workshop agenda and the preparation of the manuscript. Marc W. Cavaillé-Coll, MD contributed to the planning and organization of the workshop; contributed to the preparation of the manuscript. Shukal Bala, PhD contributed to the planning and organization of the workshop; contributed to the preparation of the manuscript. Ozlem A. Belen, MD contributed to the planning and organization of the workshop; contributed to the preparation of the manuscript. Yan Wang, PhD contributed to the planning and organization of the workshop; contributed to the preparation of the manuscript. Renata Albrecht, MD had primary responsibility in overseeing the planning and organization of the workshop; contributed to the preparation of the manuscript and was responsible for the final approval of the version to be published. Disclosure: The authors declare no conflicts of interest. Funding: The workshop was sponsored by the FDA. No funding was received for the workshop or for the preparation of the manuscript. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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