Studies of Translation, Ethics, and Medicine, Biomedical Ethics Unit, McGill University, Montreal, Quebec, Canada.
School of Public Health, University of California, Berkeley, Berkeley.
JAMA Intern Med. 2019 Jan 1;179(1):90-97. doi: 10.1001/jamainternmed.2018.5705.
After a drug receives regulatory approval, researchers often pursue small, underpowered trials, called exploratory trials, aimed at testing additional indications. If favorable early findings from exploratory trials are not promptly followed by confirmatory trials, then physicians, patients, and payers can be left uncertain about a drug's clinical value (clinical agnosticism). Such findings may encourage the off-label use of ineffective drugs.
To characterize the relationship between exploratory and confirmatory postapproval trials for the blockbuster drug, pregabalin (Lyrica).
Ovid MEDLINE and Embase databases were used to identify clinical trials published prior to January 2018 and that tested the efficacy of pregabalin for nonapproved indications. Indications, trial outcomes, publication dates, and trial design elements were recorded. Time elapsed was calculated between the generation of clinical agnosticism about pregabalin (ie, publications reporting positive or inconclusive evidence of efficacy on a primary endpoint) and it being addressed (publication of at least 1 confirmatory trial in the same indication, regardless of outcome).
There were 238 trials identified that tested the efficacy of pregabalin in at least 33 indications; 5 indications eventually received European Medicines Agency and/or US Food and Drug Administration marketing approval. Sixty-seven percent (22 of 33) of first publications for new indications may have generated clinical agnosticism. Of those indications with at least 5 years of follow-up, 63% (17 of 27) may have generated agnosticism that was not addressed in confirmatory trials within 5 years. As pregabalin development expanded from indications that received regulatory approval to other indications, the linkage of exploratory to confirmatory trial publication diminished.
After initial approval, exploratory evidence suggesting the value of pregabalin for new indications often went unconfirmed for extended periods of time. Poor coordination between exploratory and confirmatory testing may represent an important vehicle through which off-label prescription is recommended in clinical practice guidelines and encouraged in the absence of confirmatory trial evidence.
药物获得监管批准后，研究人员通常会进行小型、效力不足的试验，称为探索性试验，旨在测试其他适应症。如果探索性试验的早期有利发现没有及时跟进确证性试验，那么医生、患者和支付者可能会对药物的临床价值（临床不确定性）感到不确定。这些发现可能会鼓励对无效药物的超说明书使用。
描述重磅药物普瑞巴林（Lyrica）的探索性和确证性上市后试验之间的关系。
使用 Ovid MEDLINE 和 Embase 数据库，确定了截至 2018 年 1 月之前发表的测试普瑞巴林用于非批准适应症的疗效的临床试验。记录了适应症、试验结果、发表日期和试验设计要素。计算了普瑞巴林出现临床不确定性（即报告主要终点疗效阳性或不确定证据的出版物）到解决不确定性（在同一适应症中发表至少 1 项确证性试验，无论结果如何）之间的时间间隔。
共确定了 238 项试验，测试了普瑞巴林在至少 33 种适应症中的疗效；5 种适应症最终获得了欧洲药品管理局和/或美国食品和药物管理局的营销批准。新适应症的首次出版物中有 67%（33 个中的 22 个）可能产生了临床不确定性。在至少有 5 年随访的适应症中，有 63%（27 个中的 17 个）可能出现了未在 5 年内通过确证性试验确认的不确定性。随着普瑞巴林的开发从获得监管批准的适应症扩展到其他适应症，探索性试验与确证性试验发表的联系减弱。
最初批准后，对于新适应症的探索性证据表明普瑞巴林的价值，往往在很长一段时间内没有得到确认。探索性和确证性试验之间的协调不佳可能是一个重要的途径，通过这个途径，超说明书处方在临床实践指南中被推荐，并在没有确证性试验证据的情况下被鼓励。
