In the effort to reduce attrition rates and improve approval rates of new molecular entities by regulatory agencies, there's no doubt that biomarkers can make a big impact. But it's not as simple as tacking on additional studies. Biomarker development requires an insightful strategy and consideration of specific opportunities and needs throughout the drug development pipeline.
A quality biomarker starts at the source-the sample itself. Sample collection and handling protocols must be standardized to specify the minimum volume requirement in the proper container along with the most optimal temperature during transportation and storage. These requirements should be backed and driven by validated processes. To further ensure biomarker stability, it's equally critical to include the maximum allowed time in transportation.
Any slip in the process can introduce external variability and reduce the validity of results. Building in end-to-end oversight and control ensures harmonized sample handling and transportation protocols to maximize data yield and minimize variability.
For example, the outcome of isolating peripheral blood mononuclear cells (PBMCs) from whole blood is very dependent on transportation time and temperature changes. Depending on temperature levels and fluctuations, as well as the total time in transportation, cell yield and recovery can vary up to 40%and cell functions can be impacted; potentially questioning the validity of downstream biomarker test results.
Beyond quality samples, a biomarker development strategy must also factor in the right level of validation. With too little, the test might not reveal sufficient information and data may not be robust enough to meet regulatory requirements. On the other extreme, excessive validation can unnecessarily squander resources and cost. Fit-for-purpose validation adapts to both the phase of development and the desired outcomes to create the optimal level of evaluation.
At the stage of unregulated pre-clinical feasibility testing, a simple assessment of the biomarker test can provide valuable go/no-go decisions while advanced validations can provide comprehensive assessment suitable for regulatory requirements in pre-clinical (GLP) or clinical settings (GCP, CAP/CLIA).
Studies will likely require more than one laboratory setting, highlighting the importance of reducing biases between labs and among instruments. Therefore, it is crucial to demonstrate initial correlation and monitor the "combinability" of data over time from multiple sources. Survey samples, a sample exchange program and/or a robust inter-lab QC program can provide this necessary information.
Depending on the phase of development and the role of the biomarker, the timelines for biomarker assay development and/or validation can greatly vary. While it can only takes a few weeks to develop a custom assay for non-regulated work, developing the same test in a CAP/CLIA environment can take several months to satisfy stringent regulations. Likewise, Lab Developed Tests (LDT) will usually require more time than In Vitro Diagnostics (IVD) tests.
Proactive planning is especially important when disease state samples are needed for validation. For example, locating and collecting samples for a Minimal Residual Disease (MRD) test in leukemia patients can be quite difficult. In this situation, the method validation processes should account for an extended timeline and adjust the downstream dependencies accordingly.
When it comes to sample management in biomarker development, a bit of foresight goes a long way. Consider the value of retrospective, prospective and bridging studies in the late stages of a clinical trial. Having relevant samples on hand with their corresponding data is particularly important and can drastically reduce the need for costly rework.
Storing and making use of these samples requires smart biobanking, where the sample is secure and its physical characteristics are electronically accessible. Here, it's important to identify and keep only the necessary samples to minimize waste and cost.
Biobanked samples retain the most value with their associated laboratory test results and patient clinical information, tracked throughout their lifetime. Therefore, it's essential to keep the appropriate patient consent for use in additional studies beyond an individual trial as well as to leverage the right IT solutions to make the most of these precious samples.
While not every development process leads to a companion diagnostic (CDx), starting with a strong biomarker strategy creates an inherent advantage. From emerging exploratory work to early phases of a clinical trial, all the relevant data can be transferred and put to use toward companion diagnostic development.
Even if the development is running in parallel, both the pharmaceutical company and the CDx vendor have different end goals. Strong project management provided by the CRO partner must define and unite expectations early in the process. Bolstered by a clear definition of roles and responsibilities, the teams can better communicate and coordinate joint efforts on the path to a companion diagnostic.
With so many factors to consider in biomarker development, there is no single turnkey solution. But with early and strategic planning, biomarkers will accelerate the delivery of safer, less costly treatments and ultimately transform the healthcare landscape.