NEW YORK – While the US Food and Drug Administration's recent final rule on laboratory-developed tests (LDTs) most directly impacts the clinical lab industry, in vitro diagnostic companies will likely also feel effects from the new regulation.

纽约——虽然美国食品和药物管理局最近关于实验室开发测试（LDT）的最终规定最直接地影响了临床实验室行业，但体外诊断公司也可能会受到新法规的影响。

In particular, new FDA requirements around modifying IVDs could lead labs to push IVD vendors to validate their tests across a wider variety of use cases, potentially creating new customer expectations and competitive dynamics.

特别是，FDA关于修改IVD的新要求可能会导致实验室推动IVD供应商在更广泛的用例中验证其测试，从而可能产生新的客户期望和竞争动态。

Labs modify FDA-approved assays for a variety of reasons including to change a test's reportable range, to change its intended use populations, or to use it in a different sample type. When a lab makes such a modification, the modified test then becomes an LDT. During a presentation at the recent Association for Diagnostics & Laboratory Medicine's (ADLM) annual meeting, Patricia Jones, clinical director of the chemistry and metabolic disease labs at Children's Medical Center of Dallas, noted that 'modifying existing FDA assays is the second most common reason for running an LDT.'.

实验室出于多种原因修改FDA批准的检测方法，包括改变检测的可报告范围，改变其预期使用人群，或将其用于不同的样品类型。当实验室进行这样的修改时，修改后的测试就会变成LDT。达拉斯儿童医学中心化学和代谢疾病实验室的临床主任帕特里夏·琼斯在最近的诊断与实验医学协会（ADLM）年会上发表演讲时指出，“修改现有的FDA检测方法是运行LDT的第二大最常见原因。”。

The FDA's rule on LDTs complicates this relatively common practice, as certain modifications will now require a lab to take the modified test through premarket review. In the preamble to the final rule, the FDA listed several kinds of modifications to existing LDTs that would require premarket review: changes to the indications for use; changes to the operating principle of the test; a switch to a 'significantly different technology,' such as the addition of AI or moving from targeted to whole-genome sequencing, from immunoassay to mass spectrometry, or from manual to automated testing; or 'adversely' changing the test's 'performance or safety specifications.'.

FDA关于LDT的规定使这种相对普遍的做法变得复杂，因为某些修改现在需要实验室通过上市前审查进行修改后的测试。在最终规则的序言中，FDA列出了对现有LDT的几种修改，这些修改需要上市前审查：改变使用适应症；；转向“显着不同的技术”，例如添加AI或从靶向测序转向全基因组测序，从免疫测定转向质谱，或从手动测试转向自动测试；或“不利地”改变测试的“性能或安全规范”。

Exactly what test modifications will trigger the FDA's premarket review requirements remains uncertain, but the LDT rule will likely complicate labs' decisions around when to modify a test. It could also come to impact lab decisions around IVD vendors and equipment purchases as vendor tests and platforms may differ with, for instance, one vendor offering an assay cleared in one sample type and a second vendor offering the same test but cleared in a different sample type..

究竟什么样的测试修改会触发FDA的上市前审查要求仍然不确定，但LDT规则可能会使实验室在何时修改测试的决定复杂化。这也可能会影响IVD供应商和设备采购的实验室决策，因为供应商测试和平台可能不同，例如，一个供应商提供一种样品类型的检测方法，另一个供应商提供相同的测试方法，但在不同的样品类型中进行检测。。

At the ADLM meeting, Stephen Master, division chief and director of metabolic and advanced diagnostics at Children's Hospital of Philadelphia, offered the example of his lab, which, he noted, 'just happened to be in the process of getting all new core chemistry instruments,' meaning any previously modified assays would no longer qualify for the final rule's 'existing LDT' exemption..

在ADLM会议上，费城儿童医院代谢与高级诊断科科长兼主任斯蒂芬·马斯特（StephenMaster）举了他的实验室的例子，他指出，“该实验室碰巧正在获得所有新的核心化学仪器”，这意味着任何先前修改的检测方法都不再符合最终规则的“现有LDT”豁免。。

This presented an issue for the lab's prealbumin assay. The assay provided by its new IVD instrument vendor is approved to run in serum, but most of the lab's samples are plasma. Master said that he and his colleagues hadn't considered this a significant issue when they originally decided to switch from their previous instrument platform (which did offer a prealbumin assay approved for plasma) as they expected to simply modify the test for use in plasma.

这为实验室的前白蛋白测定提出了一个问题。新的IVD仪器供应商提供的检测方法已被批准在血清中运行，但实验室的大多数样品都是血浆。马斯特说，他和他的同事最初决定从以前的仪器平台（确实提供了一种批准用于血浆的前白蛋白测定）转换过来，因为他们希望简单地修改用于血浆的测试方法，所以他们没有考虑到这一重大问题。

Under the new LDT rule, however, they might have to take such a modified test through premarket review..

。。

Master said it is highly unlikely the lab will put in the work required to take a modified version of the test through the FDA, however. He said it is also unlikely to send out such a basic test or buy a separate platform specifically for prealbumin testing.

然而，马斯特说，实验室不太可能通过FDA进行修改版本的测试。他说，也不太可能进行这样的基本测试，也不太可能购买专门用于前白蛋白测试的单独平台。

One solution, Master suggested, could be to 'lean on the vendor' to get approvals for the various sample types his lab might need to test in.

马斯特建议，一个解决方案可能是“依靠供应商”获得实验室可能需要测试的各种样品类型的批准。

It is uncertain if and how IVD firms might respond to such requests from their lab customers. While test offerings validated in a wide variety of sample types and across different reference ranges could provide a competitive advantage for a vendor's tests and instruments, that advantage might not justify the extra investment required..

目前尚不确定IVD公司是否以及如何回应实验室客户的此类要求。虽然在各种样本类型和不同参考范围内验证的测试产品可以为供应商的测试和仪器提供竞争优势，但这种优势可能无法证明所需的额外投资是合理的。。

'I think the challenge is in figuring out what sample types to validate and where it is a competitive advantage or a real customer need,' said Donna Hochberg, a partner with Newton, Massachusetts-based healthcare consulting firm Health Advances. 'I think the manufacturers are aware this is now something that they have to pay attention to.

总部位于马萨诸塞州牛顿市的医疗保健咨询公司Health Advances的合伙人唐娜·霍克伯格（DonnaHochberg）说，我认为挑战在于找出要验证的样本类型，以及它是竞争优势还是真正的客户需求我认为制造商已经意识到这是他们必须注意的事情。

I think they have a hard road ahead to figure out where those opportunities are.'.

我认为，要想找到这些机会，他们还有一段艰难的路要走。”。

Large IVD vendors contacted by 360Dx had little to share regarding their thoughts on the issue. Roche, Siemens Healthineers, and Beckman Coulter declined to comment while Abbott did not respond to requests for comments.

360Dx联系的大型IVD供应商几乎没有分享他们对这个问题的想法。罗氏、西门子Healthineers和贝克曼·库尔特拒绝置评，而雅培没有回应置评请求。

Thermo Fisher Scientific provided a statement saying that it 'is prepared and committed to supporting our customers with research and clinical solutions designed to drive discovery and diagnose disease,' adding that its 'team of regulatory affairs experts stand ready to assist our customers to navigate the new regulatory requirements now and in the future.'.

赛默飞世尔科技公司（Thermo Fisher Scientific）发表声明说，它“准备并致力于为我们的客户提供旨在推动发现和诊断疾病的研究和临床解决方案”，并补充说，它的“监管事务专家团队随时准备帮助我们的客户在现在和未来导航新的监管要求。”。

Zach Rothstein, executive director for trade organization AdvaMedDx, whose members include a number of major IVD vendors, said that 'right now, just like the LDT community, we are still working to understand the impact of the final rule on the broader testing ecosystem and how we can continue to meet the needs of our lab partners.'.

贸易组织AdvaMedDx的执行董事扎克·罗斯坦（ZachRothstein）表示，“现在，就像LDT社区一样，我们仍在努力了解最终规则对更广泛的测试生态系统的影响，以及我们如何继续满足实验室合作伙伴的需求。”。

He added that AdvaMedDx continues to support the Verifying Accurate Leading-edge IVCT Development (VALID) Act, noting that the technical certification program included in the bill 'would enable IVD makers and LDT developers to more efficiently bring tests to patients, and that would include when the sample might need to be altered from the initial FDA clearance.' Many clinical lab players opposed VALID as they believed it would overly restrict their development and use of LDTs and hurt patient care..

他补充说，AdvaMedDx继续支持《验证准确前沿IVCT开发（VALID）法案》，并指出法案中包含的技术认证计划“将使IVD制造商和LDT开发商能够更有效地为患者进行检测，这将包括何时可能需要从最初的FDA许可中更改样本。”许多临床实验室参与者反对VALID，因为他们认为它会过度限制他们对LDT的开发和使用，并损害患者护理。。

Jonathan Genzen, chief medical officer and medical director of automation at ARUP Laboratories, said that while 'there are many vendors who recognize they are going to have to work with their customers in adapting to the final rule, I have not seen vendors who have said they anticipate increasing the number of sample types in their submissions to alleviate that work from their customers.'.

奥雅纳实验室首席医疗官兼自动化医疗总监乔纳森·根岑（JonathanGenzen）表示，虽然“有许多供应商认识到他们将不得不与客户合作以适应最终规则，但我还没有看到供应商表示他们预计会在提交的样本中增加样本类型的数量，以减轻客户的工作量。”。

He suggested that in many cases — including the prealbumin example Master detailed at the ADLM meeting — the market advantage will not be large enough to incentivize vendor investment.

他建议，在许多情况下，包括在ADLM会议上详细介绍的前白蛋白示例大师，市场优势将不足以激励供应商投资。

Hochberg suggested that vendors are unlikely to invest in FDA submissions for modified versions of assays already on the market as this will not meaningfully drive revenues. She said that for new assays, however, the calculus may change 'in terms of how you decide what sample types to validate.'

Hochberg建议，供应商不太可能投资FDA提交的市场上已经存在的改进版本的检测方法，因为这不会有意义地推动收入。她说，然而，对于新的检测方法，微积分可能会“在如何确定要验证的样本类型方面”发生变化

An IVD industry stakeholder who requested anonymity to speak about regulatory matters indicated, though, that validating in different sample types is a taxing process, noting that 'obtaining FDA clearance for a diagnostic test across multiple specimen types is exceedingly challenging for IVD manufacturers.'.

一位要求匿名谈论监管事宜的IVD行业利益相关者表示，在不同样本类型中进行验证是一个繁重的过程，并指出“获得FDA批准进行多种样本类型的诊断测试对IVD制造商来说极具挑战性。”。

Genzen offered another example of how the LDT rule could complicate vendor-lab relationships, positing a situation in which a number of labs have modified an IVD vendor's FDA-cleared test and taken those modified tests through premarket review.

Genzen提供了另一个例子，说明LDT规则如何使供应商-实验室关系复杂化，提出了一种情况，即许多实验室修改了IVD供应商的FDA批准测试，并通过上市前审查进行了这些修改后的测试。

'What are the implications if that vendor then reformulates their [underlying] assay?' he asked. 'I think [vendors] get more intertwined with the FDA submissions of their customers than they currently are, and that could create unexpected pressures or unexpected liabilities.'

“如果该供应商随后重新制定其[基础]分析，会产生什么影响？”他问道我认为（供应商）与其客户提交的食品和药物管理局（FDA）文件相比，它们之间的联系更加紧密，这可能会产生意想不到的压力或意外的责任。”

One important question is which test modifications the FDA will consider minor changes not requiring premarket review and which it will consider major changes that do require such review. In the preamble to its final rule, the agency said that it will require premarket review for modifications that 'could significantly affect the safety or effectiveness of the test or … constitute a major change or modification in intended use.'.

一个重要的问题是，FDA将考虑哪些测试修改不需要上市前审查，哪些测试修改会考虑需要进行此类审查的重大更改。在最终规则的序言中，该机构表示，它将要求对“可能严重影响测试的安全性或有效性或……构成预期用途的重大变化或修改”的修改进行上市前审查。

In its recent draft guidance on Predetermined Change Control Plans (PCCPs) — documentation manufacturers can include in initial test submissions detailing future changes they may make to the test and which allows them to make such changes without premarket review — the FDA provided some insight into how it views certain specific test modifications..

在其最近的预先确定的变更控制计划（PCCP）指南草案中，文件制造商可以在最初的测试提交中包括详细说明他们可能对测试进行的未来更改，并允许他们在没有上市前审查的情况下进行此类更改，FDA提供了一些关于它如何看待某些特定测试修改的见解。。

In one example provided in the guidance, a serum test for prostate specific antigen could be modified to use lithium heparin plasma as a sample type using a PCCP. Modifying the assay to use capillary whole blood, on the other hand, could not be done via PCCP and would require premarket review. Similarly, an IVD for measuring potassium levels in serum could be modified via PCCP to use lithium heparin plasma but not to use urine or capillary whole blood.

在指南中提供的一个例子中，可以修改前列腺特异性抗原的血清测试，以使用PCCP将肝素锂血浆用作样品类型。另一方面，修改测定以使用毛细血管全血不能通过PCCP完成，需要上市前审查。类似地，用于测量血清中钾水平的IVD可以通过PCCP修改为使用肝素锂血浆，但不使用尿液或毛细血管全血。

An extension of the potassium IVD's sample stability claims, meanwhile, could be done via PCCP..

同时，可以通过PCCP扩展钾IVD的样品稳定性声明。。