On December 20, 2016, the US Food and Drug Administration (FDA) approved labeling for use of the Dexcom G5 Mobile continuous glucose monitor (CGM) for making diabetes treatment decisions without a need for confirmation of the device’s readings with fingerstick or laboratory testing (ie, nonadjunctively).1 The FDA relabeling allowed the Centers for Medicare & Medicaid Services (CMS) to reclassify the device 3 weeks later as durable medical equipment able to replace blood glucose meters and therefore eligible for reimbursement.2 The device measures interstitial fluid glucose concentrations to estimate blood glucose concentrations. To mitigate the acknowledged risk from inaccurate estimates of blood glucose values, labeling for the device previously required a confirmation with a blood glucose meter whenever the device was used for treatment decisions, including the dosing of insulin.3 This requirement has been removed. Continuous glucose monitors have proven to be effective in improving glycemic control.4 These devices provide patients with timely alerts about impending high or low blood glucose levels, with information about the direction and speed of trends in glucose levels, and with information about an individual’s response to food and exercise. However, the recent FDA decision has potential risk for patients with diabetes who might now rely only on CGM readings for dosing insulin without confirmation of blood glucose levels. As of October 1, 2016, more than 25 000 medical device reports indicating large inaccuracies with blood glucose levels measured with the CGM device had been filed with the FDA since the start of 2015,5 shortly after FDA approval of the most recent software and sensor combination currently used by the Dexcom G5. By June 30, 2017, the number of reports of inaccuracy had increased to more than 40 000. Even though the average error of readings had steadily improved through successive generations of the device, these reports suggest that sporadic large errors still occur. Many of the reports lack detail, and approximately one-third of the concerns about inaccurate readings were attributed by the manufacturer to user error. Nonetheless, there have been detailed reports of unexplained inaccurate readings associated with loss of consciousness, seizures, car crashes, hospitalizations, intensive care unit stays, and deaths. Individually, many of the concerns raised in the reports might be regarded as unique, incomplete, or inconclusive; however, taken together, these reports represent a safety signal requiring investigation (100 examples of reports of Dexcom CGM inaccuracy appear in the Supplement). As part of the application submitted to the FDA for relabeling of the device, no new clinical evidence was introduced to address the reports of inaccuracy from numerous users. The only clinical data considered regarding the accuracy of the device were the same data that had been used originally to gain approval for using the device for diabetes treatment decisions only with verification. The data on accuracy were based on only 44 adult patients with type 1 diabetes, 7 with type 2 diabetes, and 79 pediatric patients with type 1 diabetes.6,7 Estimates of device accuracy using such small numbers of patients observed in an in-clinic setting can be overly optimistic. For example, data from the pivotal study6 for adult users, showed that when the CGM reading was greater than 80 mg/dL, there were no occurrrences in which the true blood glucose was below 60 mg/dL.3 In contrast, the Supplement includes 20 reports in which CGM values of 115 mg/dL or greater masked hypoglycemic blood glucose readings of 45 mg/dL or less that were corroborated by medical personnel, the altered consciousness of the patient, or both. An FDA advisory panel was convened in July 2016 to provide recommendations. The panel was not provided information about the large number of reports of device inaccuracy. Instead, panelists (1) heard testimonials for the device from some current users and physicians during a public hearing; (2) were presented with 2 sponsor-originated computer simulations ultimately determined unconvincing by FDA reviewers; and (3) were presented with the original clinical data. The panel also received a petition signed by users who had been told that labeling the device for nonadjunctive use was necessary to permit the CMS to provide reimbursement coverage, and would hasten the development of an artificial pancreas device. The panel voted 8-2 to approve the label changes.8 Lacking new clinical data, the FDA decision was based on (1) the advisory panel vote; (2) the testimonials, public comments to the docket, petition, and the original limited data used by the advisory panel; (3) the intent for postmarket monitoring; and (4) the expectation that a new label could mitigate risk.1 The Dexcom G5 user guide, for example, provides prominently displayed guidance to not use the CGM readings “if they do not match your symptoms or expectations.”8,9 However, it is the roughly 25% of patients with diabetes with impaired glycemic awareness for whom CGMs have been considered the most useful.3 The advice also does not serve to mitigate risk for very young patients ortheirparentswhoneedtorelyonCGMvalues,notsymptoms, to remotely monitor young children. VIEWPOINT

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FDA 批准非辅助使用连续血糖监测仪进行胰岛素给药

2016 年 12 月 20 日，美国食品和药物管理局 (FDA) 批准了使用 Dexcom G5 移动式连续血糖监测仪 (CGM) 的标签，用于制定糖尿病治疗决策，而无需通过指纹或实验室测试确认设备读数（即，非辅助性。1 FDA 重新贴标签允许医疗保险和医疗补助服务中心 (CMS) 在 3 周后将该设备重新分类为能够替代血糖仪的耐用医疗设备，因此有资格获得报销。2 该设备测量间质液葡萄糖浓度来估计血糖浓度。为了减轻因血糖值估计不准确而引起的公认风险，以前，无论何时将设备用于治疗决策，包括胰岛素的剂量，设备的标签都需要使用血糖仪进行确认。3 此要求已被删除。连续血糖监测仪已被证明可有效改善血糖控制。 4 这些设备为患者提供有关即将发生的高或低血糖水平的及时警报、有关血糖水平趋势的方向和速度的信息以及有关个人反应的信息到食物和运动。然而，最近 FDA 的决定对糖尿病患者有潜在风险，他们现在可能只依赖 CGM 读数来给药胰岛素，而无需确认血糖水平。截至 2016 年 10 月 1 日，自 2015 年初以来，在 FDA 批准 Dexcom G5 目前使用的最新软件和传感器组合后不久，已有超过 25,000 份医疗设备报告表明使用 CGM 设备测量的血糖水平存在较大误差。 . 到 2017 年 6 月 30 日，不准确报告的数量已增加到 4 万多条。 尽管通过连续几代设备读数的平均误差稳步改善，但这些报告表明仍会出现零星的大错误。许多报告缺乏细节，大约三分之一的关于读数不准确的担忧被制造商归咎于用户错误。尽管如此，仍有详细的报告称，无法解释的读数不准确，与意识丧失、癫痫发作、车祸、住院、重症监护室住院和死亡。个别地，报告中提出的许多问题可能被认为是独特的、不完整的或不确定的；然而，综合起来，这些报告代表了一个需要调查的安全信号（补充资料中出现了 100 个 Dexcom CGM 不准确报告的例子）。作为提交给 FDA 的设备重新贴标签申请的一部分，没有引入新的临床证据来解决来自众多用户的不准确报告。唯一考虑的关于设备准确性的临床数据与最初用于获得批准使用该设备进行糖尿病治疗决策的数据相同，只有经过验证。准确性数据仅基于 44 名成人 1 型糖尿病患者，7 名 2 型糖尿病患者，和 79 名患有 1 型糖尿病的儿科患者。6,7 使用在临床环境中观察到的如此少量患者对设备准确性的估计可能过于乐观。例如，针对成人用户的关键研究 6 的数据显示，当 CGM 读数大于 80 mg/dL 时，没有发生真血糖低于 60 mg/dL 的情况。3 相反，补充包括20 份报告，其中 115 mg/dL 或更高的 CGM 值掩盖了 45 mg/dL 或更低的低血糖读数，这些读数得到了医务人员、患者意识改变或两者的证实。FDA 咨询小组于 2016 年 7 月召开会议以提供建议。专家组没有得到关于大量设备不准确报告的信息。反而，小组成员 (1) 在公开听证会上听取了一些当前用户和医生对该设备的推荐；(2) 提交了 2 个发起人发起的计算机模拟，最终被 FDA 审查员认定为不令人信服；(3) 提供原始临床资料。该小组还收到了一份由用户签署的请愿书，他们被告知必须为设备贴上非辅助用途的标签，以允许 CMS 提供报销范围，并会加速人工胰腺设备的开发。该小组以 8 票对 2 票批准了标签变更。8 由于缺乏新的临床数据，FDA 的决定是基于 (1) 顾问小组投票；(2) 推荐信、对案卷、请愿书的公众评论以及顾问小组使用的原始有限数据；（三）上市后监测的意图；(4) 期望新标签可以降低风险。1 例如，Dexcom G5 用户指南提供了显着显示的指导，“如果它们不符合您的症状或期望，则不要使用 CGM 读数。”8,9 然而, 大约 25% 的血糖意识受损的糖尿病患者认为 CGM 最有用。3 该建议也无法降低非常年轻的患者或其父母需要依赖 CGM 值而不是症状远程监测幼儿的风险。观点 大约 25% 的血糖意识受损的糖尿病患者认为 CGM 对他们最有用。3 该建议也无助于降低非常年轻的患者或其父母的风险，他们需要依靠 CGM 值而非症状来远程监测幼儿。观点 大约 25% 的血糖意识受损的糖尿病患者认为 CGM 对他们最有用。3 该建议也无助于降低非常年轻的患者或其父母的风险，他们需要依靠 CGM 值而非症状来远程监测幼儿。观点