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Lack of Standardization Across MDx Infectious Disease Tests Could Undermine Pandemic Preparedness


NEW YORK ─ Among the myriad of problems in the public health space exposed during the early days of the COVID-19 pandemic is one that had been overlooked and still worries laboratorians and other experts — the lack of consumables standardization across molecular infectious disease testing platforms that could again disrupt the diagnostic workflow if another health crisis manifests.

The issue is a difficult one, however, as regulatory, competitive, and scientific factors may prevent diagnostic companies from prioritizing standardization. At the same time, how to standardize consumables and drive adoption of such standards remains unclear.

In lab areas like routine clinical chemistry, something as simple as a collection tube has been standardized for size and shape, said Jonathan Genzen, chief medical officer and medical director of automation at ARUP Laboratories. "An individual primary tube, if you put it on a chemistry instrument, chances are it is going to work on that instrument almost across the board because of the standardization we have in that area."

That level of standardization doesn't exist, however, in molecular infectious disease testing, Genzen said. "Collection tube sizes and shapes can be very different. They can have very different media that may be specific for an individual vendor or platform. And then we don't have standardization in swab sizes and shapes."

This lack of standardization makes it very difficult to automate sample processing and testing workflows, he said. This isn't a significant issue in normal times, but during the COVID-19 pandemic, when testing supplies were limited, this lack of standardization hampered labs' abilities to swap consumables from different testing platforms in and out of their automated workflows as they became available.

"Building automation that can accept many different sizes and shapes of tubes is really challenging," Genzen said.

Kelly Wroblewski, director of infectious disease programs at the Association of Public Health Laboratories, likewise said that the lack of standardization was "a huge, unanticipated issue during the pandemic."

"Having manufacturer proprietary consumables that are associated with different platforms is a challenge … and it will be a challenge in another pandemic," she said.

It will likely be a difficult problem to address, however, as molecular infectious disease test vendors have developed their tests and taken them through the regulatory process using specific consumables. Moving to different, more standardized consumables would likely require additional development and validation work and possibly new regulatory submissions.

Wroblewski noted that during the COVID-19 pandemic, the US Food and Drug Administration gave labs more flexibility than usual to mix and match molecular test components.

"However," she said, "certain reagents you would use in one assay would [sometimes] react badly and create a hazard when mixed with certain transport media. Or sometimes you would get more efficient heating with a specific type of tube based on the shape of the instrument well that the tube sits in, and you could lose sensitivity if you didn't use that particular manufacturer's product or something very similar."

There are also competitive advantages to having proprietary consumables as this can make it difficult for labs to move from a vendor's platform once they have committed to it.

While the problem is "on every laboratorian's radar," Wroblewski said she is "a bit at a loss" on how to make progress on the issue.

"There's not a lot of incentive for manufacturers to do something differently, and I'm not sure who is in a position to push doing something differently," she said.

Vijay Namasivayam, vice president of marketing, molecular lab at Roche Diagnostics, highlighted the difficulties such an effort would present to vendors, saying in an email that "standardizing components across the industry could risk innovation from manufacturers."

"Each vendor’s design is connected to unique and proprietary solutions, so true standardization for these products could be incredibly challenging," he added. "There are also factors that manufacturers face from operating in a highly regulated environment."

Angie Cheng, director of sample preparation R&D at Thermo Fisher Scientific, was less skeptical of the notion of broad standardization but likewise noted the challenges involved.

"As the industry looks to move toward standardization, we need to factor in the compatibility of different extraction reagents and automation systems, as there are numerous solution providers," she said. Pointing to transport media as an example, she noted that different ones may have different preservation capabilities, and vendors will need to understand the interfering substances that could limit the detection claims for assays.

"Ultimately, we need to understand the right metrics to evaluate to ensure we get the required specificity, robustness, and consistency," Cheng said.

Genzen said he believes some sort of external force or incentive will be necessary to move the industry toward more standardization.

"I don't say this critically, but it's not in the business and financial interests of the people selling the assays to have cross-compatibility," he said. "This has benefits. It gives you availability of assays. It gives you a reliable supply chain within the system that you own. But when things get out of control, like in a pandemic situation, you are kind of locked in, and there are benefits to greater compatibility and standardization."

The federal government is one obvious candidate for an external institution that might drive increased standardization among molecular infectious disease test vendors.

Mary Denigan-Macauley, director of health care at the US Government Accountability Office, said the office is in the early stages of an effort delegated to it under the Coronavirus Aid, Relief, and Economic Security (CARES) Act to look at "testing lessons learned," and said that standardization may be an area of interest for the GAO.

She noted that standardization and cross-compatibility were issues from the very beginning of the COVID-19 pandemic. Specifically, the molecular COVID-19 test initially developed by the US Centers for Disease Control and Prevention required use of an automated sample extraction platform that only 12 public health laboratories possessed at that time.

Ultimately, errors in the CDC's development of the test prevented its broad rollout, but even had the test worked, it would have faced implementation problems due to the fact that most public health labs did not have equipment compatible with the assay and would have had to do extraction manually, Denigan-Macauley said.

She acknowledged, though, that encouraging more standardization is a tricky challenge given that the government doesn't want to impinge on lab and vendor flexibility.

"I don't think that mandating [standardization] is necessarily the best way to go," she said.

Ambika Bumb, deputy executive director of the Bipartisan Commission on Biodefense, a privately funded organization founded in 2014 to help assess US biodefense capabilities, said that one useful role for the federal government would be to establish guidelines for what information molecular infectious disease tests should provide. She noted that currently the CDC doesn't have the authority needed to require standardized infectious disease data reporting across state and local governments.

"To have standardization and compatibility of these different consumables across these different diagnostic platforms, the government first has to provide standardization requirements defining what specific information is needed from these diagnostics," she said. "Once you define what data is needed, then you can move on to which consumables reliably provide that data, and then you can provide guidelines and standardization requirements for those platforms and consumables."

Bumb said that while the federal government might not be able to mandate increased standardization in the molecular infectious disease testing space, there are some steps it could take to encourage that process.

For instance, she said, the CDC's Laboratory Response Network could move to standardize the consumables used across its laboratories, which could push vendors who want to supply those labs to move toward those standards. Similarly, she suggested that the government could move to standardize the testing supplies it purchases for the Strategic National Stockpile.

Bumb noted, though, that while improving test standardization is an important issue for pandemic preparedness, there are many other challenges generally considered more pressing.

"It's an important problem, but there are so many problems that precede it that need to be tackled first that I don't know that it is being prioritized," she said.