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Required efficacy for novel therapies in BCG-unresponsive non-muscle invasive bladder cancer: Do current recommendations really reflect clinically meaningful outcomes?
Cancer Medicine ( IF 4 ) Pub Date : 2020-03-12 , DOI: 10.1002/cam4.2980
Marian S Wettstein 1, 2 , David Naimark 3 , Thomas Hermanns 2 , Jaime O Herrera-Caceres 1 , Ardalan Ahmad 1 , Michael A S Jewett 1 , Girish S Kulkarni 1
Affiliation  

BACKGROUND Single-arm trials are currently an accepted study design to investigate the efficacy of novel therapies (NT) in non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical Bacillus Calmette-Guérin (BCG) immunotherapy as randomized controlled trials are either unfeasible (comparator: early radical cystectomy; ERC), or unethical (comparator: placebo). To guide the design of such single-arm trials, expert groups published recommendations for clinically meaningful outcomes. The aim of this study was to quantitatively verify the appropriateness of these recommendations. METHODS We used a discrete event simulation framework in combination with a supercomputer to find the required efficacy at which a NT can compete with ERC when it comes to quality-adjusted life expectancy (QALE). In total, 24 different efficacy thresholds (including the recommendations) were investigated. RESULTS After ascertaining face validity with content experts, repeated verification, external validation, and calibration we considered our model valid. Both recommendations rarely showed an incremental benefit of the NT over ERC. In the most optimistic scenario, an increase in the IBCG recommendation by 10% and an increase in the FDA/AUA recommendation by 5% would yield results at which a NT could compete with ERC from a QALE perspective. CONCLUSIONS This simulation study demonstrated that the current recommendations regarding clinically meaningful outcomes for single-arm trials evaluating the efficacy of NT in BCG-unresponsive NMIBC may be too low. Based on our quantitative approach, we propose increasing these thresholds to at least 45%-55% at 6 months and 35% at 18-24 months (complete response rates/recurrence-free survival) to promote the development of clinically truly meaningful NT.

中文翻译:

BCG 无反应性非肌层浸润性膀胱癌新疗法所需的疗效:目前的建议是否真的反映了具有临床意义的结果?

背景 单臂试验目前是一种公认​​的研究设计,用于研究对膀胱内卡介苗 (BCG) 免疫疗法无反应的非肌肉浸润性膀胱癌 (NMIBC) 中新疗法 (NT) 的疗效,因为随机对照试验要么不可行(比较:早期根治性膀胱切除术;ERC),或不道德的(比较:安慰剂)。为了指导此类单臂试验的设计,专家组发布了具有临床意义的结果的建议。本研究的目的是定量验证这些建议的适当性。方法 我们将离散事件模拟框架与超级计算机结合使用,以找出 NT 在质量调整预期寿命 (QALE) 方面与 ERC 竞争所需的功效。总共,研究了 24 个不同的功效阈值(包括推荐)。结果 在与内容专家确定表面有效性、反复验证、外部验证和校准后,我们​​认为我们的模型是有效的。这两项建议都很少显示 NT 优于 ERC。在最乐观的情况下,IBCG 建议增加 10% 和 FDA/AUA 建议增加 5% 会产生结果,从 QALE 的角度来看,NT 可以与 ERC 竞争。结论 本模拟研究表明,目前关于评估 NT 在 BCG 无反应 NMIBC 中的疗效的单臂试验的临床意义结果的建议可能太低。基于我们的定量方法,
更新日期:2020-03-12
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