Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
KJC Statistics Ltd., Bramhall, Cheshire, UK.
Clin J Am Soc Nephrol. 2019 Mar 7;14(3):469-481. doi: 10.2215/CJN.08600718. Epub 2019 Jan 11.
IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.
IgA 肾病（IgAN）是导致终末期肾病（ESKD）的重要原因，目前尚无批准的治疗方法。评估 IgAN 治疗方法的一个挑战是，其进展到 ESKD 的通常时间过程较长。这项肾脏健康倡议项目的目的是确定替代终点，这些终点可以作为治疗对 IgAN 长期肾脏结局影响的可靠预测指标，并作为批准的基础。蛋白尿被确定为 IgAN 进展为 ESKD 的最广泛认可和研究最多的危险因素。工作组对蛋白尿减少作为替代终点来预测治疗对 IgAN 进展为 ESKD 的效果的相关数据进行了批判性评估。流行病学数据表明，蛋白尿的水平和持续时间与肾功能丧失之间存在强烈而一致的关系。来自 13 项对照试验的数据的试验水平分析也表明，蛋白尿减少的治疗效果与血清肌酐加倍、ESKD 或死亡的复合终点的治疗效果之间存在关联。我们得出结论，数据支持将蛋白尿减少作为 IgAN 进展为 ESKD 的治疗效果的合理替代终点。在美国，合理的替代终点可以作为治疗严重或危及生命的疾病（如 IgAN）的疗法加速批准的基础。根据该计划批准的产品的临床获益需要在上市后确认性试验中得到验证。
