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Parallelism: considerations for the development, validation and implementation of PK and biomarker ligand-binding assays

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The goal of this article is to discuss the fundamental key questions around parallelism assessments: why to do it, when to do it and how to do it, with consideration for different molecule types and the scientific rationale that drives different approaches. Current practices for both PK and biomarker assays regarding which samples to pick, whether to pool or not pool samples, as well as generally accepted acceptance criteria are discussed, while also highlighting the many outstanding questions that remain. In order to reach the long-term goal of understanding and developing best practices for implementation of parallelism testing for both PK and biomarker assays, industry and regulators will need to keep the conversations going, and commit to generating and reviewing data for the purposes of our own education. Means to easily share data in open forums to facilitate and build common understandings should continue and will be necessary to expedite resolution of many of these questions.

Parallelism has been a hot topic in ligand-binding assays (LBAs) in recent years. From the PK assay perspective, both regulatory guidance [1] as well as industry consensus [2–4] have weighed in with recommendations regarding the need (or not) to routinely perform parallelism assessments as part of PK assay validation. In the biomarker assay realm, parallelism assessments have long been recognized as having great utility from the early stages of method development [5,6]. In both instances, the assessment itself is similar to that employed to assess dilutional linearity. However, where dilutional linearity employs a spiked control sample to demonstrate that samples containing analyte above the assay ULOQ can be accurately measured by the assay after dilution in blank matrix, parallelism employs an incurred sample and/or samples containing endogenous analyte to demonstrate whether the sample dilution–response curve is parallel to the standard concentration–response curve [7]. For the purposes of this review, the term ‘incurred samples’ will refer to samples that contain the analyte of interest via in vivo administration of drug or samples that contain endogenous analyte.

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