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Nov 1, 2013 (Vol. 33, No. 19)

Growing Clinical Biomarker Assays

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    BioAgilytix Labs advocates communication among scientists, clinicians, and statisticians to control for variability of commercial kits and assay components.

    Choosing the optimal time to develop a companion diagnostic alongside therapeutic products can feel like aiming at a moving target. To hit the bull’s eye, one must select the appropriate assay platform for the early validation of predictive biomarkers.

    This requirement and several related challenges will be discussed at CHI’s conference on “Clinical Biomarker Assay Development.” Besides taking up the issue of choice of assay platform, presenters will discuss analytical validation strategies, reimbursement requirements, and regulatory compliance issues.

    Many pharmaceutical and biotechnology companies employ biomarker analysis for pharmacokinetic/pharmacodynamic (PK/PD) modeling. Often, companies do such evaluation utilizing commercially available assay kits. “The problem is, whether they use home-brewed or commercial kits, groups must be aware of and plan for controlling lot-to-lot kit or assay component variability. This is critical for accurate bioanalysis in support of both preclinical and clinical studies,” says Afshin Safavi, Ph.D., svp of bioanalytical operations and founder, BioAgilytix Labs.

    According to Dr. Safavi, even if groups have a validated assay, it is important to establish processes for sample analysis that minimize the effects from the kit and/or reagent variability to see the drug effectiveness. “When assessing the impact of a drug, if you are looking for 10–20% change in the biomarker, then a higher degree of assay rigor is required as opposed to expecting to see a three- to fourfold difference.”

    Controlling lot-to-lot variability is even more critical when dealing with multiyear studies. “The concept of applying correction factors between different lots of assay kits should be discussed and planned before the initiation of the project to generate quality data so the clinicians and statisticians can make the correct conclusions and decisions.”

    Since there is no standard for such control factors, each lab must set up its own quality control strategy. “Labs need to check the expiration dates of kits and have enough for studies that are expected beyond that date. At BioAgilytix Labs, we anticipate more than three months prior to changing kits or to kit expirations. We have conducted studies lasting more than three years and have found that even the same manufacturers can have lot-to-lot variations greater than 200%.”

    Dr. Safavi says the bottom line is the need for communication among scientists, clinicians, and statisticians on a project. “Groups need to spend more time in development to work out the kinks. If you do not have a robust assay, the project will suffer later.”

  • Fit-for-Purpose Assays

    In drug development, biomarker assays may serve purposes other than the ones they serve in clinical studies. This possibility has been explored by John L. Allinson, vp of biomarker laboratory services at ICON’s development solutions service division. “While diagnostic assays are used for the purpose of routine safety or efficacy assessments (under recognized global clinical laboratory accreditation schemes), there are many other uses that their versatility lends them to,” says Allinson. “These include, but are not limited to, drug candidate attrition and refinement, protocol design, dose selection, PK/PD modeling, patient stratification, companion diagnostics, post-approval surveillance, and market differentiation.

    “With such a wide range of applications, often the biomarker assay may not require as much development or long-term robustness (sometimes known as ‘exploratory’ markers and assays), while other uses may actually require more intensive attention to things like precision in parts of the analytical range not associated with significant diagnostic assessment but where more subtle changes need to be characterized, for instance, due to pharmacodynamic effects of specific drugs.”

    Allinson says that, therefore, in drug development biomarker assays, more or less attention can be applied to certain assay performance characteristics such as precision and limits of quantification. This leads to a tiered approach to assay validation in drug development assays versus a very well-established and standardized approach to diagnostic assays, which is required for their accreditation.

    Biomarker assays are not usually off-the-shelf services. “To be absolutely certain that assays are fit-for-purpose, that is, appropriate for their intended use, there must be people in the service provision who understand the assay’s clinical utility. Matching assay and technology choice to attain a suitable assay performance that enables the correct interpretation of the results to be made is absolutely critical to providing a suitable biomarker assay service. Once these decisions are made, applying a suitable fit-for-purpose validation approach to each assay is the next critical component.”

    When these careful and methodical approaches are not followed, trouble can ensue. “During my 20 years in contract research, I personally acquired knowledge of the many ways laboratories may produce data that leads to incorrect clinical decisions,” recalls Allinson. “Laboratories may modify diagnostic assays without understanding how those assays were developed.

    “An example is the replacement of calibration reference material with substances that are not recognized international reference materials. If the substances behave differently from the appropriate reference material, they can give rise to different concentration data. Depending on the use of the results, erroneous data can have very serious consequences.”

  • Precision Medicine

    The pharmaceutical and diagnostic industries are rapidly moving toward a more proactive precision medicine approach that stratifies patient populations. “Precision medicine differs from personalized medicine,” notes Shane Weber, Ph.D., director of diagnostics, clinical research, and precision medicine at Pfizer.

    “Personalized medicine seeks to help each individual patient, such as when creating a personal vaccine for a cancer patient. On the other hand, precision medicine is an approach that stratifies and segments patients into highly responding groups. An example would be KRAS mutations that underlie a variety of cancers. The use of biomarkers, diagnostics, and endo-phenotype stratification strategies are opening the door to faster and less expensive precision medicine clinical trials that will lead to therapies dramatically benefiting patients.”

    Dr. Weber says that a key question is whether early biomarker assay verification needs to be done during upstream development or in parallel with companion diagnostic clinical validation. “The answer is that both are valid. Sometimes it is possible to stratify patients early into segments. At other times it is a catch-up game—when patient trial studies reveal subsections that unexpectedly responded extremely well, while most others in the population did not. The issue is that the FDA wants biomarker verification in Phase IIa and IIb and companion diagnostic validation in Phase III.”

    The importance of correctly navigating regulatory compliance with the FDA is critical. “For example, under the FDA’s investigational device exemption process, the biomarker assay analytical verification process requires that the assay in U.S. clinical trials comply with use as an investigational use only (IUO) assay within a CLIA laboratory.”

    Ultimately, there are three major considerations to the successful development of a companion diagnostic. “The first is to coordinate with various groups at your institution to interact on the project, Dr. Weber says. “At Pfizer, for example, our biobank and diagnostic groups frequently need to interact.”

    “A second consideration is partnering. We partner outside the company with diagnostic companies that have the appropriate technology platform for the given biomarker and preferably a global commercial medical system footprint. Third, as the clinical data is generated, we continue to modify and/or stratify patient segments within the constraints of the clinical trial process in order to keep the program moving along so as to benefit patients as soon as possible.”

  • Diagnostic Platform

    The FDA defines a companion diagnostic device as one that provides information that is “essential for the safe and effective use of a corresponding therapeutic product.” When selecting the best platform for validating a companion diagnostic, one must weigh several key considerations. In addition, “…the approach for the development and approval process is dependent on each specific program,” says Ron Mazumder, Ph.D., global head of research and product development at Janssen Diagnostics. “This means that the type of biomarker and selected assay must be considered for each individual approach.”

    One key factor is assay sensitivity. “It is important to choose an assay that reflects the needed level of detection. A number of assays may show concordance, but one may be better than the other, such as TaqMan, mass spectrometry, or next-generation sequencing (NGS).”

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