Medical Device Link.

FINAL THOUGHTS

James R. Prudent, PhD, is the chief executive officer at Centrose LLC (Madison, WI). He can be reached at prudent@ centrosepharma.com.

After FDA issued new guidance requirements on September 7, 2006, the IVD market underwent some significant changes. The first in vitro diagnostic multivariate index assay (IVDMIA) was cleared February 13. The de novo 510(k) process cleared Agendia’s (Amsterdam, The Netherlands) MammaPrint, a 70-gene breast cancer prognosis test that consists of amplifying and labeling tumor RNA, microarray capture, readout and, accompanying software analysis.¹ The results and clearance reinforce the reliability of multigene tests for breast cancer prognosis prediction, but more importantly, it says that FDA is moving forward with the guidance and is making efforts to clear such devices.

Many of the other marker tests being clinically implemented appear to fall into the IVDMIA category, for example, Oncotype DX by Genomic Health Inc. (Redwood City, CA), and the AlloMap molecular expression test from XDx Inc. (Brisbane, CA). The AlloMap is not FDA cleared, but has been implemented clinically for application to cardiac allograft recipients. The test identifies the risk of tissue damage and rejection before it occurs. Like Oncotype DX, AlloMap has also been rigorously tested. XDx plans to develop the AlloMap technology into multiple IVDMIA kits.

Following the CLIA laboratory testing route, both Genomic Health and XDx developed and performed the test in-house. This particular business model causes the most concern for FDA. However, FDA has stated it believes that good science is good science, and if patients are currently receiving tests such as IVDMIAs, then the data probably exist to show that they are safe and effective. FDA hopes this perspective encourages open communication with companies and manufacturers. Also, manufacturers need to know that the first IVDMIA clearing process was very efficient with the review total time taking less than 30 days, including classification.

Building on Success

Based on mounting scientific data and the first molecular marker IVDMIAs making headlines, IVDMIAs are analyzing fewer than 100 targets per test. Tests that use more quantitative means such as real-time PCR to attain diagnosis will require even fewer markers, possibly as few as five. On average, systems using solid supports (arrays and beads) and endpoint analysis do a relatively poor job of quantifying marker concentrations, yet have greater multiplexing capabilities. Perhaps this is why MammaPrint requires more targets per test than Oncotype DX. In a previously published IVDT article, I discussed how molecular diagnostics (nucleic acid diagnostics) can be placed into two categories: 1) solid-phase highly multiplexed analysis (e.g., MammaPrint), and 2) solution-phase quantitative analysis (e.g., Oncotype DX).²

The best technologies of the future will combine the multiplexing capability of solid-phase endpoint readouts with the quantitative nature of the real-time solution- based systems. Companies like Fluidigm (South San Francisco, CA) with real-time PCR arrays may be close to achieving this system. However, there is one major concern regarding highly multiplexed real-time systems in the clinic: the number of data points. Single-target quantitative assays require a large amount of data to obtain FDA clearance, and a submission of 1000 or more real-time assays bundled into a single IVDMIA is impractical. Until the technology becomes practical, instrument systems like the Illumina (San Diego, CA) VeraCode system or the Luminex (Austin, TX) LabMap system will likely remain the standard for years to come. To extend their molecular capabilities, Luminex recently purchased TM Bioscience. With decreased revenues due to the March 13 court decision in favor of Affymetrix, Illumina may follow Luminex’s strategy and enter the IVD market by acquiring chemistry and market penetration suitable for its system.

Despite governance from FDA, the molecular market moves further ahead. FDA is taking steps to include industry representatives in the decision-making process and plans to streamline the approval process of future multiplexed IVDs. From recent public meetings, I believe their approach to be sincere, but ultimately, destiny will be in the hands of those in the ring. And that is us.

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