Including a biomarker puts extra emphasis on clinical trial planning
Biomarkers play a critical role in informing clinical strategy and supporting study-specific objectives in clinical trials. However, selecting the appropriate biomarker(s) can be a major challenge, as it impacts how the study is designed and conducted. Successful first-in-human (FIH) studies require careful coordination among sponsors, contract research organizations (CROs), monitors, and sites to overcome these obstacles.
In this article, we discuss the key questions to ask during the biomarker selection process, the operational considerations involved in including biomarkers in a study, and the importance of selecting sites with appropriate patient pools and necessary biomarker capabilities. We also explore how to transform disparate, disconnected data into actionable insights and set up a centralized biomarker database for effective decision-making.
Selecting the right biomarker for your clinical study
Biomarker selection dictates and informs clinical strategy. One of the main challenges of including biomarkers in clinical trials is determining the appropriate biomarker(s) to support the scientific and study-specific objectives. It is critical to understand how the biomarker will be used—whether as an exploratory endpoint, as a criterion to support enrollment or clinical decision-making, or as a primary or secondary endpoint—as this will impact how the study is designed and where it can be successfully conducted. Key questions to ask during the biomarker selection process include:
- Will the biomarker generate information that answers the clinical question being asked?
- Is the same or similar biomarker present in other diseases or conditions?
- How prevalent is the biomarker in the targeted patient population?
- Does prevalence vary by geography?
- Does the frequency of the biomarker vary among races or ethnicities, or does it change as the disease progresses?
- Are there validated methods for assaying the biomarker?
- If an assay needs to be developed, how will that affect the study timeline? And can that assay be scaled for later-phase studies?
Developing a deep understanding of the prevalence and potential clinical utility of the biomarker of interest can help sponsors and CROs evaluate potential geographies, sites, and investigators for inclusion in the study.
Operationalizing the inclusion of biomarkers in a clinical study
Biomarker-driven trials can be more complicated from an operational standpoint. The inclusion of biomarkers in a study often involves the collection of additional biospecimens, which may have ramifications on enrollment and informed consent, especially if the biomarker is an exploratory endpoint rather than a criterion for eligibility. Biospecimen analysis may also require contracting with specialty labs and developing well-defined processes and procedures for sample logistics.
Once an appropriate biomarker has been selected, a method for measuring and analyzing that biomarker will need to be identified. If a particular biomarker assay needs to be developed, appropriate lead time for assay development and validation needs to be built into the clinical program to mitigate the risk for delays in study start-up.
Considering a Companion Diagnostic?
Developing a biomarker-based companion diagnostic brings other considerations into play — from evaluating the diagnostic needed and the feasibility of sample collection to understanding where the test will be used and what regulators will require for approval.
Selecting sites with appropriate patient pools and necessary biomarker capabilities
Identifying and engaging with sites that have access to the population of interest and experience in biomarker-driven studies is crucial for timely study start-up. Efficient, effective site selection is a multi-step process:
Understanding biomarker prevalence using real-world data
Biomarker prevalence may vary among races, ethnicities, and even geographies, each of which can impact site selection. For example, in a recent oncology cell therapy study, eligibility was based in part on expression of human leukocyte antigen (HLA)-A*02:01. A Precision for Medicine analysis found that prevalence of HLA-A*02:01 varied in different parts of the world, ranging from 38.5-53.8% in Europe to 16.8-47.5% in North America, suggesting that Europe was the preferred geography to conduct this clinical trial.
Understanding variability in biomarker prevalence and biomarker expression can also assist study stakeholders in forecasting the number of patients and samples that need to be screened to meet enrollment targets. Review of the available literature and epidemiological data and any health economics and outcomes research (HEOR) that has been done by the sponsor may provide insight into real-world prevalence and expression of the biomarker of interest. At Precision for Medicine, we have access to the databases of both our global clinical site network and our biospecimen repository, which can be used to more efficiently identify potential sites and patients. As next generation sequencing (NGS) becomes increasingly available, it may also be possible to access blinded biomarker data to inform site selection.
Integrating biomarker requirements into feasibility evaluations
Inclusion of biomarkers in a study protocol may require sites to have access to specialized equipment or data management software. When assessing site feasibility and qualifications, it is important to consider previous experience with biomarker-driven approaches and competing studies in a similar target population that might interfere with enrollment. Key questions to ask in feasibility evaluations include:
- Does the site have experience with the disease indication?
- Does the site have experience with the biomarker of interest?
- Is the biomarker of interest part of their standard screening process today?
- Does the site have access to any equipment necessary for sample collection and analysis?
- Based on the disease indication and biomarker of interest, does the site have access to the target patient population?
Accounting for biomarker involvement in site contracts
For clinical trials that include biomarkers, it is essential for sponsors and CROs to have robust agreements with sites that allow for appropriate access to specific subject and biomarker data. Close collaboration among the sponsor, CRO, and sites could also enable sharing of blinded biomarker data that could be used to inform site selection in future clinical studies.
Transforming disparate, disconnected data into actionable insights
Biomarker-driven trials generate a substantial volume of data from a variety of biospecimens, across a variety of assay modalities, which often results in data siloes. Information on biospecimen status, such as sample collection, processing, quality, and informed consent, and biomarker assay results reside in multiple, disconnected storage locations and diverse data formats. This volume and velocity of data creates the monumental challenge of linking data across modalities and centralizing reporting for timely access to on-study decision-making.
Setting up a centralized, searchable biomarker database at the start of a trial that links clinical, biomarker, and sample data enables study teams to work together with access to a harmonized and integrated data set. Teams can acquire, quality-control (QC), and transform biomarker data, uncovering trends across subjects, time points, treatment groups, and response status.
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Real-world example: Biomarkers driving clinical and commercial decision-making
In one study, we saw a sponsor pursue a specific biomarker after seeing a group of patients experience positive interactions with the investigational product (IP). However, when starting their HEOR work, they saw the need to discuss making a change. The patients who experienced positive results had specific gene mutations—a finding that opened discussions as to whether an investment in this population was commercially viable or if a direction change was required. The biomarker selection provided enough early data to give the Sponsor confidence that their decision was the best course of action.
Conclusion
Biomarker-driven clinical trials are now mainstream, with nearly half of oncology studies and 16.5 percent of all trials incorporating biomarkers. Successful execution of such studies requires proactive strategic planning to address inherent scientific and operational challenges.
A recent analysis of 9,704 development programs from 2011 to 2020 found that trials employing a preselection of biomarkers have a two-fold higher likelihood of approval, with a nearly 50% Phase 2 success rate. With the shift toward personalized treatment of molecularly defined populations, an increasing number of clinical trials are relying on biomarker-driven approaches for identifying eligible patients or monitoring therapeutic response.
Precision for Medicine is purpose-built to accelerate therapeutic and diagnostic innovation through biomarker identification and assay development, biospecimen solutions and sample management, clinical trial services, and our proprietary sponsor-centric translational data platform, all of which work together to maximize insight into patient biology and accelerate clinical development.
