By Kirell Lakhman

AMP today said that overwrought or misguided regulation for using next-generation sequencing in the clinical lab could "limit the practice of medicine," and called for "flexible and individualized" protocols, guidelines, and controls for using the instruments in that setting.

The group also said molecular pathologists should play a role in "determining the most appropriate platform and technologies for answering the clinical question at issue."

"Optimal patient care requires the ability of molecular pathology professionals to use their professional opinion of the most suitable technological approach," Elaine Lyon, chair of AMP's Professional Relations Committee, said during a meeting on the subject that the FDA is holding in Bethesda, Md., this week.

AMP issued Lyon's comments in a press release prior to the meeting.

More broadly, FDA should seek out the opinions and recommendations of clinical molecular pathologists when deciding how to oversee next-gen sequencing applications.

"Any FDA policy to review analytical validity should include a role for the molecular pathology professionals performing the test," Lyon said. "We have an important reservoir of experience and expertise within our organization [and] we encourage the FDA to allow us to collaborate to ensure that this technology is safely, effectively, and appropriately used for the benefit of our patients."

'Still Too Soon'?

The meeting comes at a time when more and more clinical lab managers are beginning to slide off the fence on the side of next-gen sequencers and are installing platforms in their facilities.

While some, like Greg Tsongalis, chief of Dartmouth's Hitchcock Medical Center's molecular pathology clinical lab, say it's "still too soon" to begin investing in a technology that is improving and becoming more affordable so rapidly, others are diving in head-first.

Many have already shown solid data that the technology can help physicians make treatment decisions. Also, a number of test makers are striving to move the technology into clinical test development, and even other federal agencies see a glowing future for next-gen sequencing's role in clinical labs.

The next-gen trend is also picking up in Europe, where regulatory impulses for clinical use tend to be more liberal than in the US [see here, here, and here].

On the uptake side in the US, meantime, several top-shelf labs have jumped onto the next-gen-sequencing train — which is a principal reason why FDA is so eager to devise a way to evaluate sequencing-based diagnostics.

Dig this: Emory University's Genetics Laboratory last month began using its installed ABI SOLiD sequencer on clinical samples; Mayo Clinic's clinical labs "in the near future" plan to offer tests that run on next-gen instruments, a move they say will have "a significant impact" on the types of clinical tests they provide; Children's Hospital Los Angeles is developing a core facility that will use next-gen sequencers to help it diagnose and treat pediatric cancers; the Broad Institute has shown that the technology — namely, Roche's 454 GS FLX — can type human leukocyte antigens simultaneously from "many" individuals cost-effectively and accurately; and Genomic Health plans to move its molecular diagnostic-testing platform-of-choice from quantitative RT-PCR to next-gen sequencing.

Predictably, all of this movement — and mind you it's a drop in the GenomeWeb archives bucket — has caused FDA to flush with anxiety, which unfortunately but understandably is its default mode when new technologies begin appearing in clinical labs.

At the meeting, called "Ultra High Throughput Sequencing for Clinical Diagnostic Applications — Approaches to Assess Analytical Validity," AMP said that because of the growing number of platforms reaching the market in recent years, combined with their manifold applications and uses, FDA should wear kid gloves when devising its regulatory strategy for the technology.

For instance, the "performance of, and coverage needs for, a given platform are likely to differ depending on the nucleic acid analyzed, the characteristics of the DNA regions and the type of variations interrogated, the relative allele proportions of particular variants, and whether quantitative or qualitative results are desired," AMP said in the statement.

"While the analytical validity of an NGS instrument may be intrinsically very high, its data-conversion and -analysis software may have design flaws or performance limitations," it added.

As a result, before FDA can "optimally review" a particular platform, "the analytical validity of the instrument and the performance of the bioinformatics software should be evaluated both independently and as a complete system."

According to Lyon, "this necessitates flexibility and individualization in the development of validation protocols, guidelines, and controls on an application-by-application basis."

To keep the ball rolling — and to maintain some control over its direction — AMP is itself devising professional practice guidelines "to address the many ethical, social, and legal implications for the clinical use" of next-gen sequencers.

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