首页 > 资讯 > 管理临床实验室自研方法，FDA与CMS成立联合工作组寻求配合

出自识林

2015-04-19 FDA Voice

• 对于针对实验室开发的测试（LDTs），是否进行与体外诊断产品（IVD）类似的上市前审评，是业界议论的焦点。
• 在拟定的LDT监管框架下，FDA旨在强化对部分LDT质量体系和上市前审评的要求。

医保与患者均希望临床所用的实验室测试方法稳定耐用、质量可靠。

FDA于去年10月份发布了一份指南草案，提出了针对实验室开发的测试（laboratory developed tests，LDTs）的监管框架。FDA表示将与临床实验室改进修正案(Clinical Laboratory Improvement Amendments，CLIA)下负责管理临床实验室的医保和医疗服务中心 (Centers for Medicare and Medicaid Services，CMS)一道，共同监管临床实验室检测的质量。曾有同行对这两个机构的职能分工表示困惑，并关注其潜在的重复性工作。现在，为了协调两部门工作，FDA与CMS将成立联合工作组（The Diagnostic Test Working Group），以继续扩展在LDT领域的监管合作。这一工作组汇集了两部门在相关领域的主要领导与专家，旨在回应包括LDT质量要求在内的一系列问题。

虽然体外诊断产品（in vitro diagnostic products，IVD）已得到广泛的应用，但许多新的和现存的生物标记物仍缺少商业的可用试剂，这导致实验室为了满足需求而进行测试，并开发自己的检测试剂，这种不接受上市前审评的方法即为LDT。美国临床病理学会（ASCP）对LDT定义为：实验室内部研发、验证和使用，以诊断为目的的体外诊断实验。LDT仅能在研发的实验室内使用，可使用购买或自制的试剂，但这些试剂不能销售给其他实验室、医院或医生。实验室须取得临床实验室改进修正案（CLIA）标准相关认证。LDT可以用来测量或检测多种从人体中提取的样本分析物，如：蛋白质、葡萄糖、胆固醇和DNA。一些LDT相对简单，如：测量钠的含量；但现在也有日趋复杂的趋势，如：从人体的血液样本中检测出基因突变。据美国临床实验室协会的统计，已有超过一万一千家实验室被授权可以开发LDT，而他们中的大多数确实在行动了。

FDA自1976年起就获得了对体外诊断产品的监管权限，相比之下，某些现有LDT，已经在全国范围使用并带有较高风险。例如针对乳腺癌或阿兹海默症患病风险所做的某些测试，与其它接受上市前审评的体外诊断产品已十分类似。是否应对这些LDT，进行与体外诊断产品类似的上市前审评，是业界议论的焦点。在美国药监局前局长玛格丽特·汉伯格博士的卸任信中，在其总结医疗器械管理工作时，她还专门提到了对LDT监管所作的工作：“我们针对LDT提出了一个基于风险的管理机制，以帮助确保患者安全，保证供应商能够获得安全、准确、可靠的测试，同时继续推动诊断测试以帮助指导治疗决策。”但也有部分议员与业界人士对FDA扩大监管范围的行为表示了反对，他们指出扩大监管范围，可能会给实验室开发创新的测试或者成果推广制造障碍。也有人认为此类测试方法并非传统意义上的“器械”，只是针对病人的一种服务，而目前CLIA的已对此施加了有效的监管，并无必要再多加限制。

在拟定的LDT监管框架下，FDA旨在强化对部分LDT质量体系和上市前审评的要求。FDA对LDT的监管将保证这些测试的分析方法经过验证（足以精确的检出待测物），且临床应用也经过验证（能够按预设目标检出临床的情况）。FDA回顾了在指南草案公开评议期内、以及在为期两天的公开会上收到的公众建议，FDA将在发布最终指南前回应这些建议，修订监管框架。CMS，按照临床实验室改进修正案的要求，会监管实验室的工作程序而不是测试的开发工作。临床实验室改进修正案与配套文件要求建立并维护有效的实验室操作，并确保实验室聘用有资质的人员。该法案并未要求对测试进行临床前审评，或提供任何临床验证性证据。

所以，如果FDA所提的监管框架付诸实践，FDA和CMS在确保LDT质量的同一目标下都扮演着重要角色——CMA将继续按照CLIA的要求关注实验室操作与测试程序，FDA则确保实验室测试的设计和实施也应符合其对于质量体系的要求。

新成立的 FDA/CMS 工作组关注LDT质量要求的目标，还包括：

• 找出FDA质量体系管理与CLIA要求的相似之处
• 合作阐明两机构在各自工作范围内的职责
• 共用资源、避免重复、最大化效能

工作组也在探索如何在合作中实施更有效的监管，同时建立更有利于患者、医保和实验室的规程。工作组清楚业内人士关心FDA与CMS对术语的不同表述，未来将阐明这些术语，以方便实验室了解监管机构的期望。

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参考信息
[1] http://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm407296.htm
[2] http://blogs.fda.gov/fdavoice/index.php/2015/04/fda-and-cms-form-task-force-on-ldt-quality-requirements/?source=govdelivery&utm_medium=email&utm_source=govdelivery
[3] http://news.sciencemag.org/health/2014/09/fda-defends-plan-regulate-lab-developed-tests
[4] http://www.raps.org/Regulatory-Focus/News/2014/08/01/19934/In-Major-Shift-FDA-to-Regulate-Lab-Developed-Tests-as-Normal-Devices/

English Reference

Health care providers and their patients expect that laboratory tests used in clinical management of patients should be consistent and of high quality.

Under FDA's proposed framework for the oversight of laboratory developed tests (LDTs), outlined in draft guidance documents issued in October 2014, FDA would oversee the quality of these laboratory tests, alongside the Centers for Medicare and Medicaid Services (CMS), which regulate the laboratories themselves through the Clinical Laboratory Improvement Amendments (CLIA). We have heard stakeholder confusion about the roles of the two agencies in ensuring quality and concerns about potentially duplicative efforts. To coordinate efforts across the Department, FDA and CMS are establishing an interagency task force that will continue and expand on our collaboration related to the oversight of LDTs, which are tests intended for clinical use and designed, manufactured, and used within a single lab. The task force, comprised of leaders and subject matter experts from each agency, will work to address a range of issues, including those involving quality requirements for LDTs.

LDTs can be used to measure or detect a wide variety of analytes (substances such as proteins, chemical compounds like glucose or cholesterol, or DNA), in a sample taken from a human body. Some LDTs are relatively simple tests that measure single analytes, such as a test that measures the level of sodium. Other LDTs are complex and measure or detect numerous analytes. For example, DNA variations can be detected from a blood sample, which can be used to help diagnose a genetic disease. Various levels of chemicals can be measured to help diagnose a patient's state of health, such as levels of cholesterol or sodium. According to the American Clinical Laboratory Association (ACLA), more than 11,000 laboratories are authorized to develop and perform LDTs, and the majority of them do.

FDA first obtained comprehensive authority to regulate all in vitro diagnostics as devices in 1976. Some LDTs are now more complex, have a nation-wide reach and present higher risks, such as detection of risk for breast cancer and Alzheimer's disease, which are similar to those of other IVDs that have undergone premarket review.

During the lecture of Margaret A. Hamburg, M.D., Former Commissioner of Food and Drugs, She Specially introduct the progress in LDTs regulatory. We proposed a risk-based framework for laboratory developed tests (LDTs) to help ensure patients and providers have access to safe, accurate and reliable tests, while continuing to promote innovation of diagnostic tests to help guide treatment decisions.

Some lawmakers and stakeholders balk at the thought of FDA's increased involvement. Alan Mertz, president of ACLA and a witness at the FDA hearing, argued that the proposed regulations would discourage labs from developing innovative new tests and prevent them from adjusting the tests quickly for new uses. Mertz, along with several representatives, also challenged FDA's authority to regulate LDTs, arguing that they are not “devices” but rather services provided to a patient, and are already regulated effectively under CLIA.

Under the proposed LDT framework, FDA would phase in enforcement of premarket review requirements and the quality system regulation for some LDTs. FDA's oversight of LDTs will assure that the tests are both analytically valid (able to accurately detect analytes) and clinically valid (able to measure or detect the clinical condition for which the test is intended). FDA is currently reviewing public comments on the draft guidances that it received through an open public docket and a two-day public meeting. In response to public comments, FDA may modify the proposed framework when we issue final guidance.

CMS, under CLIA, oversees the labs' processes, rather than the tests they develop. CLIA and its implementing regulations include requirements for establishing and maintaining quality laboratory operations and ensuring the lab is staffed by qualified personnel. These laws do not require premarket review of tests or any evidence that a test is clinically valid.

When FDA's proposed framework is implemented, both FDA and CMS will play a role in ensuring that LDTs are high quality—CMS through CLIA by continuing to focus on laboratory operations including the testing process and FDA by enforcing compliance with the agency's quality systems regulation pertaining to the design and manufacture of the laboratory tests.

The goals of the FDA/CMS Task Force on LDT Quality Requirements include:

• identifying areas of similarity between the FDA quality system regulation and requirements under CLIA;
• working together to clarify responsibilities for laboratories that fall under the purview of both agencies; and
• leveraging joint resources to avoid duplication and maximize efficiency.

The task force is currently exploring areas where collaboration may realize greater oversight efficiency and produce the greatest benefit to patients, providers, and laboratories. The task force understands stakeholders' concerns about differences in terminology used by FDA and CMS. We intend to clarify the terms used so that labs may better understand what is expected of them.