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Clinical Prospects for Multiplex Assays


By Ken Rubenstein

January 20, 2010 | Insights | Outlook | Multiplex assays for the simultaneous measurement of multi-analyte biomarkers appear to hold great potential for myriad applications in drug development and translational research. Increasingly, although it is still very much early days, such assays may also assist in promoting wellness and compensating for genetic or epigenetic vulnerabilities.

Several factors have slowed the growth and acceptance of multiplex assays in translational research and diagnostics. Most of these factors translate to significantly added expense to develop, validate, and perform such assays. It is now common practice in pharma to use multiplex assays in the discovery and preclinical stages, with the aim of selecting one or a very few relevant biomarkers for use in translational research. In some instances, multiplex assays carry over into Phase I and II trials.

Even when five or fewer analytes constitute a biomarker, companies may choose to develop panels of individual assays using such technologies as ELISA or RT-PCR as opposed to multiplex assays using Luminex bead assays or DNA microarrays. Such a choice broadens the potential number of clinical study sites or diagnostic laboratories that have the capital equipment and trained individuals to perform the assay. Indeed, Genomic Health’s Oncotype DX assay for aiding in the selection of therapy for breast cancer detects 21 expressed genes using individual RT-PCR assays in microwell plates. The multi-analyte panel approach also allows use of already-developed assays with different technologies when available.

The now-classic method of comparing expression of a great many genes, proteins or metabolites in two or more conditions, selecting differentially expressed genes, and conducting preliminary retrospective validation studies on chosen panels has had surprisingly limited success in generating reliable assays for use in Phase III trials or as routine diagnostics. As a general observation, it seems fair to say that this prospecting approach is not likely to yield such assays. Rather, there is a growing sense that biomarkers must be chosen with some rational hypothesis in mind. Indeed, a growing number of academic researchers and even some commercial ones are moving their biomarker work in that direction.

Preclinical Biomarkers

A recent survey conducted by Insight Pharma Reports investigated practices and views on multiplex biomarkers and translational medicine—the dual subjects of the accompanying report, Multiplex Assays: Evolving Technologies, Applications, and Future Directions. Respondents were weighted heavily toward management and supervisory positions. Pharma and biopharma respondents tended more toward discovery and preclinical stages, whereas CROs and academic respondents leaned toward the clinical studies-end of the spectrum. All sectors claimed heavy involvement in both biomarker work and translational medicine.

Regarding utilization of multiplex biomarkers in drug development, the survey found extensive use in preclinical work and early clinical studies, with less frequent employment in late-stage clinical trials. Somewhat surprisingly, the desire to use multiplex rather than single-analyte biomarkers was modest but not very strong in any sector. The most prevalent reason for favoring single-analyte markers was complexity of validation. Again, surprisingly, a small majority of individuals from CROs responded that no analytical platform suitable for multiplex biomarker detection was available in-house.

Ideally, multiplex biomarkers used successfully in preclinical studies would serve the same functions in human studies. Our results suggest that while efforts have been made in that regard, results to date have been less than satisfactory. Yet there is a strong desire in all sectors for such efforts to succeed and contribute to translational efforts. Regarding future trends in multiplex biomarker usage, a strong minority in commercial sectors anticipated major increases but about half opted for moderate increases. Academic respondents were most bullish on future utilization of multiplex biomarkers.

Companion diagnostics continue to grow in popularity. About half of respondents in big pharma and biopharma indicated that their company has a drug/diagnostic combination in development. Yet the majority of these instances refer to single rather than multi-analyte biomarkers. A substantial minority felt that companion diagnostics should be considered for all programs, but more felt that they should be considered only when the need is compelling.

Regarding translational medicine functions in organizations, we found strong presence in pharma and CROs and less in biopharma where functions are often less clearly delineated than in very large companies. Views on the role of translational medicine in advancing R&D productivity tended toward moderate to strong contributions, with little support for more negative views.

Further Reading:

Multiplex Assays: Evolving Technologies, Applications, and Future Directions, by Ken Rubenstein, Ph.D., is available from Insight Pharma Reports. For more information, visit www.insightpharmareports.com/multiplex_assays.

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