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Jul 1, 2013 (Vol. 33, No. 13)

Assay Development Driving Personalized Medicine

Demonstrating clinical utility is critical for moving tests out of research-use only mode, according to this article from our July 1 issue.

  • Companion Diagnostics

    Another topic of interest is the use of laboratory-developed tests (LDTs).

    “Labs will use LTDs, particularly when developing companion diagnostics,” says John L. Allinson, vp, biomarker laboratory services, ICON Development Solutions.

    “If you look at the diagnostics we have today, at some point they were tests developed by a laboratory and not available commercially. Each individual laboratory would validate those assays for the appropriate clinical use,” Allinson says. “If you develop an in-house method because of lack of a platform to use a commercial assay, or you believe your assay is better, you still have to validate to the same degree of rigor as using an accredited diagnostic.”

    Companion diagnostics can be used to identify populations that will respond to a particular drug. In the early stages of clinical trials, they begin as a research assay used to assess certain biomarkers.

    Typically, if initial results are promising, collaborations are formed with a diagnostic company to develop the final test and platform. Working together to show clinical utility in trials, the drug-development company files the drug submission and, simultaneously, the diagnostic company files the PMA application, each depending on its own data.

    In the past, the focus has often been on single surrogate-endpoint biomarker discovery, biomarkers that substitute for the clinical endpoint. Surrogate-endpoint biomarkers are specific to one clinical condition—only about half a dozen exist to date.

    More recently, biomarker panels, which can improve specificity and sensitivity of diagnostic determinations, are being investigated. The most popular biomarkers measured today, excluding surrogate markers, provide only a part of a clinical picture, and can show changes in multiple pathologies.

    “Technology is going to drive the improvements that we see over the next few years, for instance, novel technologies that are smaller, and have the ability to measure relatively large numbers of different biomarkers, on very small samples,” Allinson says. “New technology adoption needs to be encouraged. It has real potential for positive impacts in the industry.”

  • Accounting for Variability

    Biomarker analysis is a common practice in pharmacokinetic/pharmacodynamics (PK/PD) modeling to learn about a drug’s mechanism of action.

    Biomarker assays and kits can be 510(k)-approved, lab-developed, or RUO kits. Several venders produce RUO kits. Multiple lots are generated yearly, with a shelf life less than a year. Since clinical trials can extend for years, a system is needed to link data generated from one kit lot to another.

    Each kit may contain several key components, and testing each individual reagent would be unfeasible. To address RUO kit variability, BioAgilytix Labs has implemented the concept of lot bridging.

    To quantify the kit as a unit to assure performance consistency, a series of stability QCs and fresh samples are tested over multiple days, both on the previous and new lots. A correction factor—a numerical multiplier—is generated and used to normalize the new lot with the validation, or a previous lot. Lot bridging reduces noise in the resulting data, making it more meaningful for statisticians and clinicians to interpret.

    “Even if you have a beautifully validated assay, lot-to-kit-lot variability influences results and has to be accounted for. Kit variability has nothing to do with the drug effectiveness and may point you in the wrong direction if quality data is not generated,” says Afshin Safavi, Ph.D., svp, bioanalytical operations, BioAgilytix Labs. “When you are supporting PK studies conducted under GLP, with specific regulatory requirements and guidelines, typically the drug acts as the calibrator or standard. The assays can be set up in a way that removes, or minimizes, the critical reagents lot-to-lot variability.”

    “Much biomarker work is secondary, to learn about drug mechanism of action. Calibrators and controls may, or may not, be available commercially, and may come in a variety of forms. For most biomarkers, there is no universal standard available,” Safavi adds. “Therefore, the concept of ‘fit for purpose’ is used for biomarker assay validation and analysis support.”

    “At BioAgilytix Labs, we validate the assays, treating them as if they were almost a regulated study with the proper documentation. This is how we discovered the extent of biomarker kit lot variability in the market today,” he explains. “Lot bridging becomes especially important if you want to compare studies, perform multiyear studies or add more cohorts to ongoing studies, which requires the purchase of additional kits from a different lot.”


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