Surrogate Endpoints for Late Kidney Transplantation Failure.

In kidney transplant recipients, late graft failure is often multifactorial. In addition, primary endpoints in kidney transplantation studies seek to demonstrate the short-term efficacy and safety of clinical interventions. Although such endpoints might demonstrate short-term improvement in specific aspects of graft function or incidence of rejection, such findings do not automatically translate into meaningful long-term graft survival benefits. Combining many factors into a well-validated model is therefore more likely to predict long-term outcome and better reflect the complexity of late graft failure than using single endpoints. If conditional marketing authorization could be considered for therapies that aim to improve long-term outcomes following kidney transplantation, then the surrogate endpoint for graft failure in clinical trial settings needs clearer definition. This Consensus Report considers the potential benefits and drawbacks of several candidate surrogate endpoints (including estimated glomerular filtration rate, proteinuria, histological lesions, and donor-specific anti-human leukocyte antigen antibodies) and composite scoring systems. The content was created from information prepared by a working group within the European Society for Organ Transplantation (ESOT). The group submitted a Broad Scientific Advice request to the European Medicines Agency (EMA), June 2020: the request focused on clinical trial design and endpoints in kidney transplantation. Following discussion and refinement, the EMA made final recommendations to ESOT in December 2020 regarding the potential to use surrogate endpoints in clinical studies that aim to improving late graft failure.

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Copyright © 2022 Naesens, Budde, Hilbrands, Oberbauer, Bellini, Glotz, Grinyó, Heemann, Jochmans, Pengel, Reinders, Schneeberger and Loupy.

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KB has received honoraria and/or research funding from Alexion, Astellas, Bristol Myers Squibb, Chiesi, Fresenius, Hansa, Hexal, Merck, Novartis, Otsuka, Pfizer, Roche, Sandoz, Siemens, and Veloxis. LH reports speaker fees from Astellas, consultancy and research support from Chiesi, consultancy for Novartis, and research support from Sandoz. RO has received grants/research support from Amgen, Astellas, and Chiesi; and speakers’ bureaux/honoraria from Amgen, Astellas, Chiesi, Hansa, Neovii, Novartis, and Teva. DG reports consultancy agreements and scientific boards for AstraZeneca, BMS, Hansa, and Sanofi. UH has received grants/research support from Baxter, Chiesi, and Neovii; speakers’ bureaux/honoraria from Chiesi and Hansa; and consulting fees from Astellas, Hansa, Neovii, Novartis, and Teva. IJ’s institution has received speaker’s fees from XVIVO Perfusion. MR has received lecture fees from Astellas and Chiesi; and research grant support (paid to institution) from Astellas and Chiesi for investigator-initiated studies. SS has received grants/research support from Bridge to Life, Chiesi, Neovii, Novartis, Organ Recovery Systems, and Sandoz; speakers’ bureaux/honoraria from Astellas, BMS, Chiesi, Novartis, OrganOx, and Sanofi; and consulting fees from Astellas, Atara, Merck, NefroHealth, Novartis, Sandoz, and Teva. The remaining authors declare that the work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.