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Citing Validation Costs, IP Concerns, Reference Labs Offer Gloomy Take on Protein Biomarker Tests

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VANCOUVER, BC – At the American Society for Mass Spectrometry annual meeting here this week a number of major vendors reiterated their commitment to moving their instruments into the clinic (see story this issue).

During a workshop on clinical mass spec held as part of the meeting, however, participants – including representatives from several leading reference laboratories – evinced significantly more pessimism, particularly with regard to new protein biomarkers.

Indeed, one participant, Russell Grant – strategic director and national director of mass spectrometry at Laboratory Corporation of America – said that given the high costs of protein biomarker validation as well as the recent US Supreme Court ruling against Prometheus Laboratories' patent claims on using metabolites as biomarkers for dosing thiopurine drugs (GWDN 3/20/2012), he doesn't currently "see a path" for new protein biomarkers to make their way into the clinic.

Led by Nigel Clarke and Cory Bystrom – director of mass spectrometry and associate scientific director, respectively, at Quest Diagnostics – the workshop was not intended to focus on protein biomarkers, but instead on the potential of clinical mass spectrometry in general and, specifically, the question of how it might be impacted by healthcare reform.

The discussion turned to protein biomarkers, however, in response to a question from Thermo Fisher Scientific's Dobrin Nedelkov.

The former CEO of protein biomarker firm Intrinsic Bioprobes, which was acquired last year by Thermo Fisher (PM 9/2/2011), Nedelkov asked the various reference lab representatives if they had reached any sort of consensus of the protein biomarkers they would like to see pursued.

"What is the unmet need that you guys see that nobody else has addressed?" he asked. "Do you have an agreement among the [reference lab] leaders here about assays and targets that you guys need addressed?"

In response, Bystrom observed that while large reference labs like Quest and LabCorp are certainly interested in new protein markers, "we're still waiting for the markers that look enticing enough for us to try and carry them along."

A major stumbling block, he noted, is the disconnect between academic labs who are often running low-throughput experiments with a small number of replicates and a large reference lab that can run through thousands of samples a day.

"I don't think you're going to find anybody on the reference lab side trying to chase down targets for you," added LabCorp researcher Brian Rappold. "I think that has to come from the academic side, saying that these are real biomarkers that we can now use mass spec to differentiate."

This, though, Nedelkov noted, leads back to the eternal dilemma facing protein biomarker development: "We know what we need to do. We know what [reference labs] want. But nobody is willing to do it."

The question of support for protein biomarker validation has emerged as major issue for the proteomics field. Indeed, in an interview with ProteoMonitor this week, Detlev Suckau, head of proteomics R&D at Bruker, suggested that the frustration evident at the workshop stemmed from the fact that there currently exists no sufficient system for translating protein markers from research labs to the clinic.

Ultimately, Suckau said, he believes the problem will require "certain new types of transitional medicine grants that focus on validation. The risk for the companies is too large to do that on their own. It means big money. You won't get there for $500,000 or so."

Nedelkov, too, suggested that government funding would be key to the process. However, he was somewhat more skeptical about obtaining it.

"In the past, usually the people who stepped in were the government," he said. "Is there any room for that? Is there any room for the [National] Cancer Institute [in developing these tests]?"

In this he echoed the concerns of other proteomics researchers who have, in recent months, criticized US government proteomics initiatives – the second stage of the NCI's Clinical Proteomic Technologies for Cancer initiative, in particular – for continuing to focus resources on protein biomarker discovery as opposed to validation and implementation (PM 2/17/2012).

In the absence of government funding, however, it appears unlikely the large reference labs will step into the breach. "We're not risk averse," Quest's Clarke said. "But we have to answer to our shareholders. We have to be careful about that."

"We have naturally been a small "r" big "D" kind of company," he said, referring to research and development. "So we look to the academic community to come to us with good ideas, and they do. But the trouble is we get these assays brought to us where they've got a [sample size] of 6 or 10, and it's so early on, and we have to put a huge amount of resources into it to then be able to see if it even works."

And, added Grant, the recent US Supreme Court decision invalidating Prometheus Laboratories' patents for using metabolites as biomarkers for drug dosing have made reference labs even more wary of investing heavily in development of protein biomarker tests.

"The Prometheus decision has changed the landscape for mass spectrometry," he said. The decision "potentially means that you can't put IP around [marker panels.] So what does that mean to us as an industry? Biomarker ideas driven by mass spectrometry discovery, executed in a mass spectrometry setting ... I don't see a mechanism to make that happen."

Not everyone was so gloomy about mass spec-based protein biomarkers moving into the clinic. For instance, in response to Nedelkov's initial question, Alan Rockwood, scientific director of the mass spectrometry laboratory at ARUP Laboratories, suggested several areas where mass spec measurements could replace existing tests – including for a range of peptide hormones and for hemoglobinopathies.

So far as new protein biomarker tests were concerned, however, pessimism ruled the day.

"The problem is that with the gap between what can be done right now in a very esoteric research setting [and what can be done in a reference lab], there's no clear path yet for us to carry this forward," Bystrom said. "So there's still technology that's missing. Better, faster mass spectrometers; workflows that have been optimized better."

"There are some very significant challenges, and I don't see a path, not for new biomarkers," Grant said. "Yet."

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