Date Published: February 8, 2016
Publisher: Springer US
Author(s): Prajakti A. Kothare, Kevin P. Bateman, Marissa Dockendorf, Julie Stone, Yang Xu, Eric Woolf, Lisa A. Shipley.
Dried blood spot (DBS) sample collection has gained increased interest across the pharmaceutical industry as a potential alternative to plasma for pharmacokinetic (PK) evaluations. However, regulatory guidelines and examples of late-stage clinical trial applications in the literature are lacking. This paper communicates Merck’s strategy for the implementation of DBS exemplified by experience on a late-stage program (MK-8931). In this program, DBS was proposed as the sole matrix for phase 3 studies to decrease logistical burden in an aging target patient population (Alzheimer’s disease). In vitro and bioanalytical tests demonstrated initial method feasibility and suitability for further evaluations in the clinic. An in vivo dataset was developed initially in healthy subjects (phase 1 study) and then in patients (phase 2/3 study) to establish a quantitative relationship between the blood and plasma concentrations (bridging dataset) using descriptive and population PK analyses. This allowed for PK conclusions to be seamlessly drawn across the clinical program without impact from the choice of matrix. This integrated information package (in vitro, bioanalytical and clinical) was presented to major regulatory agencies (FDA and EMA) for regulatory input. Based on this package, regulatory concurrence was gained on accepting DBS as the sole matrix in late-stage clinical trials.
Since its original application for the detection of phenylketonuria in neonates half a century ago, dried blood spots (DBS) have gained popularity as a screening tool for various diagnostic tests including metabolic disorders, therapeutic drug monitoring, and HIV infection in neonates (1–3). The pharmaceutical industry and regulators have continued to explore the potential of DBS as a viable alternate matrix for pharmacokinetic analyses (4–6). DBS was initially evaluated at Merck in 2001 for discovery stage PK studies and subsequently implemented for the pediatric development program of an anti-HIV compound in 2009. Since then, a number of compounds have been evaluated for initial in vitro and bioanalytical feasibility to implement DBS. A subset of these has progressed to implementation of DBS in clinical trials, including late-stage clinical trials. Strategically, Merck has chosen to primarily focus the application of DBS towards late-stage patient studies (phase 2 and/or 3) where it has the potential to render greater impact. In our opinion, the value proposition for DBS from a clinical perspective is as follows:To add flexibility in the collection of PK data in phases 2 and 3 studies: Typically, sparse PK samples in phases 2 and 3 studies are constrained to limited time windows during a clinic visit. DBS, particularly in an out-patient setting, expands the window for access to such data. This may be especially beneficial for drugs with long half-lives or long acting formulations to evaluate steady-state or time for washout, or where clinical endpoints are collected by patient-completed diaries or are episodic (e.g., migraine, asthma, or erectile dysfunction trials). However, sampling methods in an out-patient setting need to mature further to gain adequate precision for pharmacokinetic modeling.Decreased patient burden (blood volume) in vulnerable populations: The smaller sample volumes typically associated with DBS (three spots of ∼20–40 μL each) vs. typical plasma samples (∼200–1000 μL) are clinically attractive for vulnerable populations where blood volumes are a clinical or ethical concern (e.g., younger pediatric or elderly populations). However, DBS should not be considered an automatic choice for studies in such populations. Equal consideration should be given to liquid microsampling approaches.Improved logistical feasibility: DBS sampling offers a number of logistical advantages (e.g., ambient temperature storage or shipping, no need for specialized equipment such as refrigerated centrifuges and simplified sample preparation) that may reduce operational burden associated with PK sampling in larger multi-center patient trials and lead to potential cost savings. A reduced operational burden may encourage greater participation of clinical sites for PK evaluation in phases 2 or 3 trials, and thereby enrich the database for characterization of the population pharmacokinetics and exposure-response relationships. Prior to implementing ambient shipping for DBS, the extended stability of DBS samples should be established to ensure integrity of the samples.
The strategy for using DBS in clinical programs at Merck has been developed over several years and has been a non-linear process. Merck arrived at its current state by looking at DBS holistically in the context of individual development programs, avoiding a one-size-fits-all approach. Early efforts mainly focused on analytical aspects, and it was only after a whole program approach was adopted, which the broader utility of DBS has started to be realized. Merck’s strategy requires a prospective and multi-study approach to build the data sets to enable successful clinical implementation. As such, the alignment of all groups (analytical, pharmacokinetics, clinical, operations) involved is critical to the successful implementation of DBS. The input from regulatory agencies has been critical to the refinement of our strategy. The feedback on both the analytical and pharmacokinetic aspects demonstrated scientific insightfulness and curiosity, while embracing a forward-looking attitude. As with any new approach, Merck anticipates unexpected hurdles during the development and implementation stages. Learning from the large-scale implementation of DBS in these trials is likely to benefit the broader community and will be the subject of future disseminations.