BLOODPAC's collaborations with European Union liquid biopsy initiatives

Abstract

The adoption of liquid biopsy into clinical practice has revolutionized the landscape of cancer diagnostics and treatment monitoring. In the U.S., the Blood Profiling Atlas in Cancer (BLOODPAC) has significantly supported the advancement of these technologies through consensus building [1]. In collaboration with the United States (US) Food and Drug Administration (FDA), BLOODPAC has developed minimum technical data elements (MTDEs) and analytical validation protocols to streamline the assay development and regulatory assessment of liquid biopsy-based technologies. Additionally, BLOODPAC has established a pre-competitive data sharing model to support clinical implementation.

The European Union faces regulatory and access challenges that hinder widespread adoption of liquid biopsy technologies. Complexities under the In Vitro Diagnostic Regulation (IVDR) and Clinical Trials Regulation (CTR) have introduced variability and delays across member states. While recognizing Europe's strengths in developing robust frameworks and high standards for advancing precision oncology, this paper explores how BLOODPAC's efforts—particularly in standardization, validation, and data sharing—could inform and complement EU initiatives. BLOODPAC's experience in developing fit-for-purpose validation frameworks and fostering regulatory-industry dialogue offers particularly relevant insights for addressing EU-specific challenges. This paper proposes opportunities for collaboration and guidance development that could enhance European access to liquid biopsy-based tests for precision medicine, ultimately improving patient access and outcomes for cancer care and management.

1. Introduction

As precision medicine becomes increasingly central to oncology, liquid biopsy technologies—particularly those leveraging circulating tumor DNA (ctDNA)—are reshaping how cancer is diagnosed and monitored. These minimally invasive tools offer the potential for earlier detection, dynamic treatment monitoring, and broader access to genomic profiling.

In the United States (US), the clinical utility of liquid biopsy was formally recognized with the US Food and Drug Administration's (FDA) first approval of a ctDNA-based assay in 2016 [2]. This milestone catalyzed further progress through collaborative efforts such as the Blood Profiling Atlas in Cancer (BLOODPAC), a consortium that has advanced the validation and standardization of liquid biopsy assays through engagement with the FDA and the broader scientific community.

In contrast, the European Union (EU) has acknowledged the clinical promise of liquid biopsy—as reflected in the 2022 recommendations from the European Society for Medical Oncology (ESMO) which advocated for the use of ctDNA assays [3]—but faces regulatory hurdles that complicate widespread adoption. The practical adoption of liquid biopsy across the EU is constrained by the intricate and sometimes time-intensive regulatory processes defined by the In Vitro Diagnostic Regulation (IVDR) [4]. Medicinal product clinical trials that utilize liquid biopsy tests interventionally and/or to confirm clinical performance of the test must meet IVDR requirements in parallel to the requirements of the Clinical Trials Regulation (CTR) [5]. The validation of liquid biopsy results for use as clinical trial endpoints also requires acceptance by KOL's, medical societies and regulators. Unlike the US FDA's unified approach to reviewing and approving diagnostic technologies, the EU regulatory landscape presents distinct challenges through the IVDR and CTR frameworks that collectively influence how liquid biopsy technologies reach European patients. In particular, varied interpretations of regulatory requirements for performance studies, lack of availability of a coordinated regulatory assessment processes, and stricter post-market performance and surveillance requirements have introduced uncertainties, potentially delaying patient access to these technologies in the EU. In addition, the path for reimbursement of ctDNA assays varies considerably across Member States.

This paper explores how BLOODPAC's initiatives in the U.S.—including standardized technical protocols, validation frameworks, and data sharing tools—can inform and potentially support the EU's efforts to integrate liquid biopsy technologies into clinical care. By drawing on BLOODPAC's regulatory collaboration experience, this paper identifies opportunities for global synergy aimed at accelerating patient access to precision oncology solutions.

2. BLOODPAC's contributions to advancing liquid biopsy technologies in the United States (U.S.)

BLOODPAC is a collaborator-funded organization with the mission to accelerate the development, validation and clinical use of liquid biopsy tests to better inform medical decisions and improve patient care and outcomes.

Through strategic partnerships—such as with the U.S. Food and Drug Administration (FDA)—BLOODPAC has pioneered key tools and frameworks that address regulatory, technical, and data-sharing barriers. These contributions offer a scalable model for international adoption and present particular relevance as the European Union (EU) navigates implementation of the IVDR and CTR frameworks.

BLOODPAC's work is most evident in four core areas: (1) standardization of preanalytical variables, (2) analytical validation of ctDNA-based assays, (3) development of frameworks for emerging liquid biopsy applications, and (4) infrastructure for secure, collaborative data sharing.

2.1. Development of minimum technical data elements (MTDEs) for preanalytical variable standardization

To address variability in pre-analytical processes, BLOODPAC's introduction of MTDEs represents a significant stride in harmonizing the preanalytical phase of liquid biopsy research. These MTDEs encompass a comprehensive set of guidelines that define blood sample collection, handling, and storage. These uniform protocols decrease variability and improve the integrity of data, creating a meticulous approach to standardization that can not only enhance the reproducibility of liquid biopsy tests but also foster their wider acceptance and integration into routine clinical practice [6]. Through regular and member-wide reviews, BLOODPAC continues to ensure the MTDEs are relevant and globally harmonized. In a recent landscape analysis, it was determined the BLOODPAC recommendations align with all relevant International Organization for Standardization (ISO) standards, addressing the critical need for standardized, high-quality sample handling to ensure patient safety, data integrity, and successful regulatory review [7].

2.2. Development of analytical validation protocols for ctDNA comprehensive genomic profiling

BLOODPAC's Analytical Variables Working Group developed consensus-based guidelines to standardize the analytical validation of ctDNA-based next-generation sequencing (NGS) assays [8]. These guidelines address critical aspects of assay performance, including sensitivity, specificity, and reproducibility. By setting these rigorous benchmarks, BLOODPAC has facilitated the consistent evaluation of ctDNA assays by assay developers and regulatory authorities, ensuring they meet the high standards required for clinical application. These comprehensive validation guidelines provide structured approaches to generate robust performance data to satisfy analytic requirements in the IVDR.

2.3. Development of frameworks and analytical validation protocols for other clinical applications of liquid biopsy

BLOODPAC's collaborative efforts also focus on patient tumor characterization by extending into the field of Molecular Residual Disease (MRD) detection and Multi-cancer Detection (MCD). Recognizing the growing importance of sensitive and accurate MRD detection in patient management, BLOODPAC is developing guidelines to establish analytical and clinical performance measures for MRD detection. These guidelines address unique challenges in MRD testing, including the need for standardized terminology and definitions to promote consistency across studies and reports. The goal is to create assays capable of detecting the minimal levels of tumor-derived DNA that indicate residual disease, thereby providing clinicians with critical information for patient management. Similarly, the development and discussion of appropriate risk frameworks for MCD assays was published to help accelerate the design and development of clinical utility studies [9]. These initiatives are expected to streamline the regulatory approval process for additional liquid biopsy clinical applications. By providing consensus frameworks and unified language, patient outcomes will be improved by enabling more precise and timely interventions across multiple cancer types and treatment modalities.

2.4. Evolution of data infrastructure: from the Data Commons to the BLOODPAC portal

BLOODPAC developed the Data Commons, a centralized repository that streamlines the aggregation and dissemination of liquid biopsy data [10]. This platform enables a diverse array of users, including researchers, clinicians, and industry professionals, to share and access a wealth of information. The Data Commons significantly bolsters the transparency of research findings and expedites the process of biomarker discovery and validation. It is particularly instrumental in advancing the characterization of patients' tumors, offering a rich resource for the identification of novel biomarkers and the refinement of personalized medicine strategies.

Building on this success, BLOODPAC is now transitioning from the Data Commons to the BLOODPAC Portal. The BLOODPAC Portal is a comprehensive public resource that enables the scientific community to store, share and analyze liquid biopsy datasets with associated publications seamlessly. BLOODPAC's goal is to develop the Portal into a centralized knowledge resource, aggregating liquid biopsy publications and datasets to benefit both BLOODPAC members and the broader community.

3. European initiatives advancing liquid biopsy technologies

In parallel with overarching guidance from the Medical Device Coordination Group on in vitro diagnostics (MDCG IVD), numerous European organizations are advancing the clinical integration of liquid biopsy technologies. These initiatives address critical components of the diagnostic pipeline—from standardizing blood collection protocols and validating next-generation sequencing assays to driving biomarker discovery and promoting regulatory harmonization. While not exhaustive, Table 1 highlights select contributors that exemplify the breadth and depth of efforts underway to support the adoption of liquid biopsy across the European Union.

Table 1.

[Organizational contributions to the advancement of liquid biopsy ].

ORGANIZATION	DESCRIPTION
BLOODPAC	BLOODPAC is a non-profit organization with the goal to accelerate the development, validation and clinical use of liquid biopsy tests to better inform medical decisions to improve outcomes of patients with cancer. Their Global Regulatory and Accessibility Working Groups collaborate with EU IVDR and CTR experts to catalyze a U.S.-EU project aimed at enhancing patient access and integrating liquid biopsy into cancer care across Europe. Learn more here.
European Coalition for Access to Comprehensive Genomic Profiling (ECGP)	ECGP brings together key stakeholders in Europe, including patients, clinicians, pathologists and industry to identify and share best practices, and develop evidence-based policy recommendations on the clinical and economic utility of CGP for payers and other decision-makers. Its initiatives include advocating for both tissue and liquid biopsy CGP to inform treatment decisions and improve cancer care in Europe. Learn more here.
EUROPEAN COMMITTEE FOR STANDARDIZATION (CEN)	CEN facilitates the development of European Standards, for industries, including medical diagnostics. It has led efforts to establish CEN/TS 17390–3:2020, focusing on the analytical staining of circulating tumor cells (CTCs). This specification is part of a broader set of preanalytical standards for liquid biopsy, alongside ISO 20186–3:2019, which addresses the isolation of circulating cell-free DNA (ccfDNA) from plasma. Learn more here.
EUROPEAN CONFEDERATION OF PHARMACEUTICAL ENTREPRENEURS (EUCOPE)	EUCOPE is Europe's trade body that gives a bigger voice to small and mid-sized innovative companies working in the field of biopharmaceuticals and medical technologies. EUCOPE collaborates with BLOODPAC and other stakeholders to push for the adoption of liquid biopsy in Europe, advocating for regulatory frameworks and standards that support its integration into cancer diagnostics and treatment Learn more here.
EUROPEAN LIQUID BIOPSY SOCIETY (ELBS)	The ELBS aims to ensure that liquid biopsy (LB) tests soon become part of clinical routine to benefit cancer patients (<5 years). It is our mission to promote comprehensive research on liquid biopsy leading to robust LB assays that are subsequently validated in clinical trials providing evidence for the clinical utility of LB. Learn more here.
EUROPEAN ORGANIZATION FOR RESEARCH AND TREATMENT OF CANCER (EORTC)	EORTC aims ultimately to increase people's survival and quality of life by testing new therapeutic strategies based on existing drugs, surgery, and radiotherapy. EORTC also helps develop new drugs and approaches in partnership with the pharmaceutical industry and in patients' best interests. Some of the ongoing initiatives by EORTC include the EORTC MRD Task Force, MRD Clinical Validation and Clinical Utility Studies, the Response Evaluation Criteria in Solid Tumors (RECIST) Working Group, and the SPECTA Platform. Learn more here.
EUROPE’S BEATING CANCER PLAN	Europe's Beating Cancer Plan prioritizes cancer, including cancer in women, with policy actions, research efforts, and unprecedented funding. For example, the SHINE project within this plan has developed a proof of concept for the rapid detection of breast cancer from a blood droplet, advancing liquid biopsy technologies in Europe. Learn more here.
INTERNATIONAL QUALITY NETWORK FOR PATHOLOGY (IQN PATH)	IQN Path is an international multi-stakeholder expert group focused on improving quality of clinical biomarker testing. IQN Path brings together organizations and key stakeholders involved in quality implementation. Some of the ongoing initiatives by IQN Path include Adoption of Cancer Omics and Precision Oncology in the patient's journey and Pilot EQA for cfDNA Testing for Multiple Markers. Learn more here.
INTERNATIONAL SOCIETY OF LIQUID BIOPSY (ISLB)	ISLB was founded in 2017 with an aspiring objective: to become the scientific reference in Liquid Biopsy and the unique link of all stakeholders in the LB theme. ISLB connects liquid biopsy professionals globally. In Europe, it provides a platform for sharing best practices and fostering collaboration among researchers and clinicians to advance the clinical use of liquid biopsy in cancer diagnostics and monitoring. Learn more here.
MEDICAL DEVICE COORDINATION GROUP (MDCG)	The MDCG provides regulatory guidance to support the uniform application of the Medical Devices Regulation (MDR) and In Vitro Diagnostic Regulation (IVDR) across EU Member States. While there are currently no liquid biopsy-specific MDCG guidelines, existing MDCG guidance documents on IVD classification, clinical evidence requirements, and performance studies are commonly applied to liquid biopsy technologies. In the absence of dedicated guidance, these general documents serve as the de facto reference for regulatory expectations related to liquid biopsy assays. Learn more here.
MEDTECH EUROPE	MedTech Europe is the European trade association for the medical technology industry, advocating for access to innovative technologies. Recently, with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and BioMed Alliance, they published a position paper calling for a reconsideration of Article 58.1(a) of the IVDR. They argue that routine venous and capillary blood draws should not face the same strict standards as invasive procedures, which would reduce delays and improve access to liquid biopsy and other diagnostics in Europe. Learn more here.
THE NATIONAL INSTITUTE FOR BIOLOGICAL STANDARDS AND CONTROL (NIBSC)	NIBSC, an agency of the Medicines and Healthcare products Regulatory Agency (MHRA), is responsible for developing biological standards and reference materials. Endorsed by the WHO Expert Committee on Biological Standards (ECBS) in 2018, NIBSC is developing ctDNA primary standards, initially for EGFR variants. Learn more here.
EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY (ESMO)	ESMO is a leading professional organization for oncologists, dedicated to advancing the practice of medical oncology through education, research, and collaboration. ESMO provides a platform for sharing knowledge, fostering best practices, and supporting cancer care worldwide. In 2022, the ESMO Precision Medicine Working Group convened a group of experts to provide recommendations on various aspects of ctDNA testing, drawing on the latest published literature to guide its application in cancer diagnosis and treatment. Learn more here.

∗The materials in this table are not comprehensive. This is a high-level overview of groups participating in bringing liquid biopsy to patients in Europe, this table is not intended to be an exhaustive list.

4. Bridging the gap: Proposed synergies between BLOODPAC and European Union initiatives

The European Union has made notable progress in advancing liquid biopsy technologies, despite navigating a complex and evolving regulatory landscape. With initiatives emerging across member states, a unified approach remains essential to ensure consistency, reduce duplication, and speed clinical adoption. The EU's collective efforts, combined with BLOODPAC's initiatives, can help accelerate global access to liquid biopsy technologies. BLOODPAC's work in aiding regulatory bodies around the world to find common ground promises to positively reshape the challenging landscape created by evolving regulatory expectations, including the IVDR and CTR. A harmonized approach could streamline the adoption of liquid biopsy, thereby facilitating consistency among regulators including EU member states, educating Notified Bodies, arriving at common frameworks for Health Technology Assessments (HTA), and increasing investment in biomarker research.

While the European Commission provides guidelines and validation standards to ensure the safety, effectiveness, and quality of in vitro diagnostic devices, specific guidance for liquid biopsy technologies remains limited, potentially delaying their market entry and clinical adoption. A liquid biopsy diagnostic test typically requires conformity assessment by a Notified Body under the IVDR depending on its intended clinical use. Additionally, a clinical performance study application may be required when using an IVD that is not Conformité Européenne (CE) marked depending on the intended purpose in the clinical study. To receive a companion diagnostic (CDx) designation following the clinical performance study, a consultation between the Notified Body and the European Medicines Agency (EMA) is required. Understanding the regulatory and reimbursement pathways are crucial to formulating strategies that are in line with EU standards and promote the uptake of cutting-edge diagnostics like liquid biopsy.

While the EU regulatory environment differs from that of the US, the principles and methodologies developed by BLOODPAC could be adapted accordingly. In collaboration with partners in the EU, BLOODPAC recommends the following areas of synergy to accelerate the use of liquid biopsy globally.

• a.Harmonizing minimum technical data elements (MTDEs) for preanalytical processing to ensure data traceability.

  BLOODPAC's minimum technical data elements (MTDEs) for preanalytical processing provide a critical foundation for data traceability and standardization. These include specifications for blood collection tube type, sample composition, shipping and storage temperatures, time to fractionation, and time to freezing—factors that directly impact data quality and reproducibility. These are particularly relevant to the IVDR's Annex II [11] on technical documentation, which mandates detailed descriptions of specimen type, handling, and storage. These standardized elements are crucial for generating high-quality and comparable data, aligning with the IVDR's aim to reduce variability and ensure consistency. Moreover, documentation of preanalytical variables—such as time to fractionation and time to freezing—as required by the MTDEs enhances traceability and data quality. This directly supports the generation of valid clinical evidence, in line with the requirements for clinical performance studies under IVDR Annex XIII, and complements the technical documentation obligations under Annex II related to specimen handling and stability.

  Importantly, these standardized elements help mitigate discrepancies in blood draw practices, which can vary widely and are sometimes subject to differing interpretations under the IVDR. For example, blood draws from standard-of-care procedures may be classified as invasive and require a performance study application depending on the member state. Position papers from groups like MedTech Europe [12] have begun addressing such issues, and further harmonization—supported by BLOODPAC's framework—could reduce barriers and support broader adoption as well as inform common specifications for liquid biopsy tests for adoption by the European Commission.

• b.Utilize protocols developed in collaboration with regulatory bodies to streamline analytical performance study design.

  BLOODPAC's collaboration with the U.S. Food and Drug Administration (FDA) to develop analytical validation protocols for ctDNA-based assays has established performance benchmarks essential for test development. These protocols, which address key parameters such as Limit of Detection (LoD), reproducibility, specificity, sensitivity, and interference—are in line with the IVDR's General Safety and Performance Requirements (GSPRs) in Annex I.

  The potential for these protocols to be adapted to the EU regulatory environment under the IVDR is significant and could be used to streamline the conformity assessment process of liquid biopsy tests. This approach could mitigate challenges such as limited Notified Body capacity and regulatory discrepancies, accelerating the adoption of validated and approved assays for genomic profiling in clinical practice and medicinal product trials across the EU. These protocols could also ensure that liquid biopsy tests are suitable for investigational and research purposes, particularly in advanced solid tumor applications making them ideal for inclusion in clinical performance study plans to facilitate submissions to ethics committees and competent authorities.

  Finally, BLOODPAC's ongoing efforts on MRD detection protocols highlight the importance of biomarker research for patient characterization beyond therapy selection [13]. These protocols aim to standardize methodologies for detecting molecular residual disease, which is critical for therapy decision and adaptation, post-treatment monitoring and long-term patient management. By adopting similar frameworks in the EU, initiatives like European Liquid Biopsy Society (ELBS), the International Society of Liquid Biopsy (ISLB) and Joint Action Personalized Cancer Medicine (JA PCM) could strengthen support for non-therapeutic biomarker research, addressing the current lack of regulatory guidance and funding in this area.

• c.Utilize the BLOODPAC Portal to freely share liquid biopsy clinical data.

  BLOODPAC's achievements in standardizing preanalytical processes and promoting collaboration through platforms like the BLOODPAC Portal could be instrumental in the EU. The BLOODPAC Portal stands as a model for secure data management and reproducibility of liquid biopsy results, which is essential for maintaining the integrity of clinical evidence in accordance with EU regulations. The platform's commitment to transparency and reproducibility aligns with the EU's requirements on clinical evidence.

  This approach could greatly benefit projects like CAN.HEAL and CANCER-ID, which have the potential to make strides in biomarker research for early detection and disease monitoring. These projects could benefit from participating in BLOODPAC's data-sharing platform and collaborative frameworks. Strategies could be developed to overcome common challenges, ensuring that biomarker research extends beyond therapy selection to include patient characterization and long-term disease management. Moreover, the BLOODPAC Portal's analytical tools provide a rigorous assessment of preanalytical variables enhancing standardization and validation processes.

  This standardized approach helps to generate evidence that meets the regulatory requirements for technical documentation and performance evaluation in the EU. By promoting standardization and harmonization consistent with evolving regulatory requirements, the BLOODPAC Portal could be instrumental in advancing liquid biopsy technologies within clinical settings while reducing duplicative efforts in assay validation.

5. Conclusions and next steps

As liquid biopsy technologies continue to evolve, global collaboration and regulatory alignment are essential to accelerate their clinical adoption. BLOODPAC has established a strong foundation through its data-sharing platforms and validated protocols, offering a regulatory-ready framework that can support harmonized implementation across borders.

Adapting BLOODPAC's protocols to align with EU regulatory requirements presents a significant opportunity to accelerate harmonized implementation. Strengthening collaboration between BLOODPAC and EU partners, including the European Commission and patients advocacy groups and the International Medical Device Regulators Forum (IMDRF), will be key for the provisional global adoption of these protocols. This harmonization will not only benefit patients by providing quicker access to innovative diagnostic tools but will also support the medical community and industry members by reducing complexity and fostering international collaboration.

Additionally, joint development of guidelines for performance studies of liquid biopsy technologies would address a critical gap in the regulatory frameworks across international boundaries while ensuring methodological standardization and reproducibility. In conclusion, by leveraging the groundwork laid by BLOODPAC and working in concert with EU and international regulatory bodies, a cohesive and dynamic pathway for the adoption of these life-changing technologies can be created. The next steps require continued dialogue, shared learning, and a unified commitment to refining and harmonizing guidelines that will ultimately lead to improved patient outcomes and elevates the global standard of cancer care.

Ethical approval/Patient consent

No ethical approvals or patient consent were necessary for the study.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lauren C. Leiman reports administrative support, article publishing charges, and writing assistance were provided by BLOODPAC. Abde Abukhdeir reports a relationship with AstraZeneca that includes: equity or stocks. Banu Saritas-Yildirim reports a relationship with Natera Inc that includes: equity or stocks. Elaine Katrivanos reports a relationship with Tempus AI, Inc. that includes: equity or stocks. Haydar Celik reports a relationship with Bristol-Myers Squibb Company that includes: equity or stocks. Ingrid Mehlhorn reports a relationship with Exact Sciences Corporation that includes: equity or stocks. Jose Luis Costa reports a relationship with Thermo Fisher Scientific Inc that includes: equity or stocks. Michael Wierzba reports a relationship with GSK that includes: equity or stocks. Robert Dumanois reports a relationship with Thermo Fisher Scientific Inc that includes: equity or stocks. Veronica Gonzales reports a relationship with MSD that includes: equity or stocks. Given his role as honorary editor, Christian Rolfo had no involvement in the peer-review of this article and has no involvement in the peer review of this article and has no access to information regarding its peer review. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.