Understanding effectiveness of new drugs in older adults shortly after market entry

当一种新药进入市场时，比较有效性证据通常仅由证据组成。 来自随机临床试验（RCT），这些试验获得了监管机构的批准。老年人是主要 药物和其他治疗药物的消费者，在随机临床试验中代表性不足。期间 在新药进入市场后的关键早期，来自RCT的证据可能无法反映平均水平。 实际治疗的患者类型的经验，并且“真实的世界”经验的积累不足， 纵向医疗保健数据库，用于生成强大的证据。 在这一关键时刻，结合证据可以加强对新药净效益的理解， 实际上得到治疗的老年人和病人。然而，适当的整合方法 用于指导临床实践的上市前RCT和早期上市后比较有效性证据尚未 尚未被确认。我们将在三个案例研究中探讨这些问题。对于每个案例研究，我们将获得 来自上市前RCT的个体水平数据，并创建由新药物启动者组成的观察性队列 使用Medicare数据的药物和对照药物。我们将评估结合联合收割机证据的不同方法 从RCT中生成，“真实的世界”证据来自Medicare中老年人常规护理中观察到的数据 在新药的早期和后期上市经验中。这些方法包括复杂的 加权以及交叉设计综合方法，这些方法结合了来自RCT和“真实的世界”数据的联合收割机信息。 具体而言，我们将研究：（1）如何创新性地应用方法来联合收割机结合个人层面的数据 来自上市前RCT和早期上市后观察数据的数据加速了对有效性的理解， 在RCT中通常代表性不足的老年患者中，新上市药物的安全性？(2)如何 我们能否评价和理解上市前RCT中治疗效果估计值差异的原因 上市后早期的观察数据？ 该项目将产生一个框架，用于将上市前RCT和早期上市后证据相结合， 旨在加速了解患有多种合并症的老年人的治疗有效性。使用 这一框架将提供早期的见解和临床指导，老年病学家使用新药， 患者进入市场后不久。由于本项目中使用的方法旨在提供早期 反映实际治疗的患者类型（和亚型）的平均有效性的证据， 常规护理，而不是平均有效性的参与者的试验，该项目的影响将是 特别是对于针对老年人的新药，病情较重的患者通常在试验中代表性不足。

When a new drug enters the market, comparative effectiveness evidence is often comprised solely of evidence from the randomized clinical trials (RCTs) which led to regulatory agency approval. Older adults are major consumers of drugs and other therapeutics and underrepresented in randomized clinical trials. During the critical early period after a new drug enters the market, evidence from RCTs may not reflect the average experience for the types of patients actually treated and there is insufficient accrual of ‘real world’ experience in longitudinal healthcare databases for robust evidence generation. At this critical juncture, combining evidence can enhance understanding of net benefit of new drugs in the older, sicker populations who are actually treated in practice. However, appropriate methods for integrating pre-market RCT and early post-market comparative effectiveness evidence to guide clinical practice have not yet been identified. We will explore these issues in three case studies. For each case study, we will obtain individual level data from pre-market RCTs and create observational cohorts comprised of initiators of the new drug and comparator using Medicare data. We will evaluate different methods which combine evidence generated from RCT with ‘real world’ evidence from data observed in routine care of older adults in Medicare during early as well as later post-market experience with the new drugs. These methods include complex weighting as well as cross-design synthesis methods that combine information from RCT and ‘real world’ data. Specifically we will research: (1) How can innovative application of methods to combine individual-level data from pre-market RCTs and early post-market observational data accelerate understanding of effectiveness and safety of new to market medications in older patients who are typically underrepresented in RCTs? (2) How can we evaluate and understand reasons for differences in treatment effect estimates from pre-market RCTs and observational data in the early post-market time period? This project will produce a framework for combining pre-market RCT and early post-market evidence as a means to accelerate understanding of treatment effectiveness in older adults with multiple comorbidities. Use of this framework will provide early insights and clinical guidance to geriatricians on use of new drugs in their patients shortly after market entry. Because the methods used in this project are designed to provide early evidence that reflect average effectiveness in the types (and subtypes) of patients actually treated as part of routine care as opposed to average effectiveness in participants of a trial, the impact of this project will be particularly profound for new medications that target older, sicker patients typically underrepresented in trials.