Pediatric Lung Transplant Outcomes Based on Immunosuppressive Regimen at Discharge: Retrospective Cohort Study Using Real-World Evidence From the US Scientific Registry of Transplant Recipients.

BACKGROUND: This retrospective analysis of the US Scientific Registry of Transplant Recipients was undertaken to obtain real-world evidence concerning the efficacy and safety of tacrolimus-based immunosuppression in pediatric lung transplant recipients to support a supplemental New Drug Application. METHODS: Overall, 725 pediatric recipients of a primary deceased-donor lung transplant between January 1, 1999, and December 31, 2017, were followed for up to 3 years post-transplant based on an immunosuppressive regimen at hospital discharge: immediate-release tacrolimus (TAC)+mycophenolate mofetil (MMF), TAC+azathioprine (AZA), cyclosporine (CsA)+MMF, or CsA+AZA. The primary outcome was the composite endpoint of graft failure or death (all-cause) at 1 year post-transplant, calculated by Kaplan-Meier analysis. RESULTS: The use of TAC+MMF increased over time. During 2010 to 2017, 91.7% of pediatric lung transplant recipients were receiving TAC+MMF at the time of discharge. The proportion of recipients continuing their discharge regimen at 1 year post-transplant was 83.7% with TAC+MMF and 40.4% to 59.7% with the other regimens. Cumulative incidence of the composite endpoint of graft failure or death at 1 year post-transplant was 7.7% with TAC+MMF, 13.9% with TAC+AZA, 8.9% with CsA+MMF, and 9.1% with CsA+AZA. There was no significant difference in the risk of graft failure or death at 1 year post-transplant between groups from 1999 to 2005 (the only era when adequate numbers on each regimen allowed statistical comparison). No increase in hospitalization for infection or malignancy was seen with TAC+MMF. CONCLUSION: The real-world evidence from the US database of transplant recipients supported the Food and Drug Administration's approval of tacrolimus-based maintenance immunosuppression in pediatric lung transplant recipients.

Incidence, prevalence, and treatment of anemia of non-dialysis-dependent chronic kidney disease: A retrospective database study in France.

BACKGROUND: Minimal data are available regarding the prevalence and incidence of anemia among patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) in France. METHODS: This was a retrospective non-interventional study of patients with a record of NDD-CKD in the Echantillon Généraliste des Bénéficiaires (EGB) database between January 01, 2012, and December 31, 2017. The primary objective was to estimate the annual incidence and prevalence of anemia of NDD-CKD. Secondary objectives included description of the demographics and clinical characteristics of patients with NDD-CKD-related anemia. An exploratory objective was to use machine learning to identify patients from the general population that might have NDD-CKD but without a recorded ICD-10 diagnosis of CKD. RESULTS: During 2012-2017, 9865 adult patients in the EGB database had confirmed NDD-CKD; of these, 49.1% (4848/9865) had anemia. From 2015 to 2017, estimates of incidence (108.7-114.7 per 1000 population) and prevalence (435.7-449.5 per 1000 population) of NDD-CKD-related anemia were stable. Less than half of patients with anemia of NDD-CKD were treated with oral iron, and approximately 15% were treated with erythropoiesis-stimulating agents. Based on adult French population projections in 2020 and an estimated prevalence rate in 2017 of 42.2 per 1000 population for confirmed plus possible NDD-CKD (as a proportion of the general French population), the estimated number of patients with possible NDD-CKD in France was 2,256,274, approximately five-fold greater than the number identified by diagnostic codes and hospitalizations. CONCLUSIONS: Anemia of NDD-CKD was shown to be a constant long-term burden in France, and its apparent prevalence may still be significantly underestimated. Given the potential treatment gap, additional initiatives to better identify and treat NDD-CKD anemia may improve patient management and treatment outcomes.

Lung Transplant Outcomes in Adults in the United States: Retrospective Cohort Study Using Real-world Evidence from the SRTR.

BACKGROUND: The Scientific Registry of Transplant Recipients was retrospectively analyzed to provide real-world evidence of the efficacy and safety of tacrolimus-based immunosuppressive regimens in adult lung transplant recipients in the United States. METHODS: Adult recipients (N = 25 355; ≥18 y) of a primary deceased-donor lung transplant between January 1, 1999, and December 31, 2017, were followed for 3 y posttransplant based on immunosuppressive regimen at discharge: immediate-release tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), cyclosporine (CsA) + MMF, or CsA + AZA. The primary outcome was the composite endpoint of graft failure or death (all-cause) at 1 y posttransplant (calculated via a modified Kaplan-Meier method). RESULTS: Discharge immunosuppressive regimens in lung transplant recipients changed over time, with a substantial increase in the use of TAC + MMF. TAC + MMF was the most common immunosuppressive regimen (received by 61.0% of individuals at discharge). The cumulative incidence of graft failure or death at 1 y posttransplant in adult lung transplant patients receiving TAC + MMF was 8.6% (95% confidence interval 8.1-9.1). Risk of graft failure or death was significantly higher in adults receiving CsA + MMF or CsA + AZA compared with TAC + MMF, with no significant difference seen between TAC + MMF and TAC + AZA. TAC + MMF had the highest continued use at 1 y posttransplant (72.0% versus 35.4%-51.5% for the other regimens). There was no increase in the rate of infection or malignancy in the TAC + MMF group. CONCLUSIONS: Real-world evidence from the most comprehensive database of transplant recipients in the United States supports the use of TAC in combination with MMF or AZA as maintenance immunosuppression in adult lung transplant recipients.

Minimizing Patient Burden Through the Use of Historical Subject-Level Data in Innovative Confirmatory Clinical Trials: Review of Methods and Opportunities.

The goal of clinical trial research is to deliver safe and efficacious new treatments to patients in need in a timely and cost-effective manner. There is precedent in using historical control data to reduce the number of concurrent control subjects required in developing medicines for rare diseases and other areas of unmet need. The purpose of this paper is to provide a review for a regulatory and industry audience of the current state of relevant statistical methods, and of the uptake of these approaches and the opportunities for broader use of historical data in confirmatory clinical trials. General principles to consider when incorporating historical control data in a new trial are presented. Bayesian and frequentist approaches are outlined including how the operating characteristics for such a trial can be obtained. Finally, examples of approved new treatments that incorporated historical controls in their confirmatory trials are presented.