A Novel Approach to Examine Within-Class Therapeutic Exchangeability of Medications

尽管几乎完全缺乏头对头随机对照试验的充分数据， 治疗指南和处方药保险处方集通常考虑 药物分类同样有效，同样安全。然而，关于治疗的错误假设 交换会使患者暴露于次优治疗和不良临床结果，尤其是老年患者， 成年人，他们受慢性病的影响不成比例，是最大的人均消费者， 处方药尽管其具有重大的临床和经济意义， 仍然是一个明显研究不足的问题，目前没有可行的解决方案。我们因此 为同类药物的治疗互换性评价提供了一种新的、可行的方法。的 拟议的研究将利用医疗保险D部分结构所创建的自然实验， 药物福利和D部分计划从制造商那里获得的可变财政激励。因为计划- 具体的处方集管理策略，开始使用新药的D部分入组者通常面临 同一类别内替代药物的自付费用不同。自付费用的差异 在数百种D部分计划中， （四）因为这些经济激励强烈影响一类药物对另一类药物的选择， 独立于患者的临床特征（如强有力的初步数据所证明的），它们有助于 有效的IV估计。从原始病历和死亡原因数据中验证结局， 国家死亡指数进一步提高了研究的严谨性。利用现有的数据，超过2200万医疗保险受益人，拟议的研究将审查4个精心挑选的药物类别，以建立一个新的方法， 根据观察性数据系统评估类内治疗交换的框架： 1)直接口服抗凝剂（DOAC）用于预防房颤或房扑的卒中，2）二肽 肽酶4抑制剂（DPP-4s）用于2型糖尿病，3）高效他汀类药物用于动脉粥样硬化性心血管（CV）疾病的二级预防，4）钠-葡萄糖协同转运蛋白-2抑制剂（SGLT-2s）用于2型糖尿病 糖尿病这些是根据明确的标准选择的：D部分受益人的高使用率，不确定性 关于类内的治疗交换，替代治疗之间的自付费用有足够的差异， 代理人，以及有效衡量医疗保险索赔结果的能力。我们包括了有很强先验的例子 对比（DPP-4和CV结局）和（SGLT-2和截肢）类内差异，以显示我们 可以再现预期的发现，以及差异不确定的其他发现（例如，DOAC和缺血性 中风）。该提案开始了一项非常有前途的新颖工作，可以可行地产生有效和批判性的成果 在老年人中广泛使用的药物类别中，需要关于治疗交换的证据， 为未来的验证性研究奠定基础，并改善临床医学、患者预后和公共卫生。

Despite almost complete absence of adequate data from head-to-head randomized controlled trials, treatment guidelines and prescription drug insurance formularies typically consider individual drugs within medication classes as equally effective and equally safe. Yet, incorrect assumptions regarding therapeutic exchangeability expose patients to suboptimal treatments and adverse clinical outcomes, particularly older adults, who are disproportionately affected by chronic conditions and are the largest per capita consumers of prescription medications. Despite its substantial clinical and economic implications, therapeutic exchangeability remains remarkably understudied and represents a problem without a feasible current solution. We thus propose a novel and feasible approach to evaluate the therapeutic exchangeability of same-class drugs. The proposed studies will take advantage of natural experiments created by the structure of the Medicare Part D drug benefit and the variable financial incentives that Part D plans receive from manufacturers. Due to plan- specific formulary management strategies, Part D enrollees initiating a new medication often face substantially different out-of-pocket costs for alternative drugs within the same class. The differences in out-of-pocket costs among alternative same-class drugs among the hundreds of Part D plans will serve as instrumental variables (IVs). Because these financial incentives strongly affect the choice of one drug of a class over another and are independent of the patients’ clinical characteristics (as demonstrated by strong preliminary data), they facilitate valid IV estimation. Outcome validation from primary medical records and cause of death data from the National Death Index further improve the rigor of the study. Using existing data on >22 million Medicare beneficiaries, the proposed study will examine 4 carefully selected drug classes to establish a new methodological framework for the systematic assessment of within-class therapeutic exchangeability from observational data: 1) direct oral anticoagulants (DOACs) for stroke prevention in atrial fibrillation or atrial flutter, 2) dipeptidyl peptidase 4-inhibitors (DPP-4s) for type 2 diabetes, 3) high potency statins for secondary prevention of atherosclerotic cardiovascular (CV) disease, and 4) sodium-glucose co-transporter-2 inhibitors (SGLT-2s) for type 2 diabetes. These were selected based on explicit criteria: high rates of use in Part D beneficiaries, uncertainty about therapeutic exchangeability within the class, sufficient variation in out-of-pocket costs among alternative agents, and ability to validly measure outcomes in Medicare claims. We included examples with strong priors against (DPP-4s and CV outcomes) and for (SGLT-2s and amputations) within-class differences to show we can reproduce expected findings, and others for which differences are uncertain (e.g., DOACs and ischemic stroke). This proposal begins a highly promising novel line of work to feasibly generate valid and critically needed evidence on therapeutic exchangeability within widely-used drug classes among older adults, serve as the basis for future confirmatory studies, and improve clinical medicine, patient outcomes, and public health.