Collaborative Infrastructure

The Analytical Validation working group has collaborated to generate the Generic Analytical Validation Protocols for Cell-Free Assay Performance Verification v1.0, designed to provide test developers/manufacturers with a baseline of standardized protocols with which to document the analytical performance of a cell-free DNA assay. The generic protocols are intended for use by developers and manufacturers of  blood-based liquid biopsy in vitro diagnostic tests for oncology, regulatory bodies and clinical laboratories. The protocols were formally reviewed by the FDA via the agency’s Pre-Submission process and published in the September 2020 issue of Clinical Chemistry. Establishing this vital industry standard will enable test developers to streamline their efforts to align with the FDA during their proposed product’s Pre-Submission phase and help minimize the time spent by FDA reviewers on guiding test developers through the process. As follow up deliverables, the working group is focusing on two additional protocol documents, including: 

• Molecular Residual Disease (MRD) Analytical Validation— Jimmy Lin (Freenome)

  BLOODPAC formed the MRD Analytical Validation Working Group (BLOODPAC MRD AV WG) to develop a set of generic analytical validation protocols for blood-based Molecular Residual Disease (MRD) testing of solid tumors. The BLOODPAC MRD AV WG recognizes that the end goal of MRD testing for oncology is to provide diagnostic information for the presence of disease following a clinical intervention as well as recurrence, and for this information to help inform specific decisions as evidence supports over the course of the patient journey for improved outcomes and to reduce costs associated with treatment of disease recurrence.

• bTMB Analytical Validation — Mark Sausen (Personal Genome Diagnostics)

  BLOODPAC formed the bTMB Analytical Validation Working Group (BLOODPAC bTMB AV WG), at the request of Friends of Cancer Research. The group was charged with drafting a supplement to the original v1.0 document such that the v1.1 document also contained the information and protocols required to perform analytical validation of bTMB tests. BLOODPAC bTMB AV WG recognizes that there are numerous approaches for design of a Comprehensive Genomic Panel (CGP) to assess bTMB for solid tumors currently under development, and attention is focused on increasing standardization and advancing best practices. As every test is unique, it is suggested that the guidance developed by BLOODPAC should serve as a generic foundation from which test-specific validation strategies can evolve.

This newly established working group exploring liquid biopsy for brain tumors will first aim to identify key preanalytical variables relevant for cerebrospinal fluid (CSF) ctDNA genomic profiling and begin the process of establishing a CSF dataset within the BLOODPAC Data Commons. The team is composed of a wide range of participants spanning clinical neuro-oncology, academia, and industry. Our members include scientists from the Memorial Sloan Kettering Cancer Center, Thermo Fisher Scientific, Massachusetts General Hospital, Penn State, Focused Ultrasound Foundation, Inivata, and USC. The group's overarching long-range goal is to establish liquid biopsy for routine clinical use in primary brain tumors, initially focusing on CSF and eventually expanding to blood.

This newly established Working Group focused on Clonal Hematopoiesis of Indeterminate Potential (CHIP) aims to address gaps in CHIP terminology, standardize the evaluation of CHIP detection techniques, and recommend concepts guiding the utility of this biomarker in clinical and translational applications. The team will undertake the standardization of the lexicon and definitions around CHIP, establish criteria for its classification as a biomarker, and standardize the method concepts for CHIP detection, including techniques such as matched buffy coat, algorithmic, and gene frequency analysis.

The goals of the Early Cancer Detection and Screening Working Group are to develop and build consensus around common definitions and standardized frameworks for evidence development relevant to novel blood-based technologies for early cancer detection. The field of early cancer detection lacks a common lexicon, and standards for evidence generation in areas such as clinical validation and clinical utility. By creating a forum for industry, academic, non-profit, policy, regulatory, and reimbursement leaders in this area, the Working Group will articulate and align upon these key issues for blood-based early detection tests targeting single or multiple cancers. The Working Group will disseminate their work as peer-reviewed publications further supporting the advancement of this space.

The JUST FREAKING DO IT! working group aims to increase quality and consistency of ctDNA analysis through inter-laboratory testing of well-recognized analytical tools and reference materials. JFDI testing will include measurements of accuracy and precision, as well as other metrics fundamental to ctDNA analysis. The JFDI team includes ten independent laboratories (all BLOODPAC members) with interest in improving standardization and reliability of ctDNA testing, an essential step as an increasing number of clinical decisions have the potential to be based on liquid biopsy. The working group just published a report sharing the results of this analytical study–the full publication can be found here.

The goal of the Molecular Residual Disease (MRD) Strategic Steering group is to identify and address barriers to the implementation of MRD in solid tumors in non-metastatic disease, and to develop projects and resources to address these challenges. The working group’s long-term aim is to validate MRD as an early endpoint in solid tumors. The Strategic group organizes and advises the efforts of three subgroups — MRD Clinical Validation, MRD Analytical Validation, and MRD RDE— with the overall goal of addressing specific barriers to MRD adoption and utilization in clinical trials and medical practice. The Strategic Steering group is currently developing a lexicon to standardize terms related to MRD testing and create a controlled vocabulary. The lexicon is intended to assist manufacturers, clinicians and pharmaceutical companies in the field build upon work to date and form a common framework for the different applications and uses of MRD.

• MRD Clinical Validation
  Co-chairs: Dan Norton (Personalis) & Carol Pena (Merck)
  This newly created group is working on mapping the path forward for clinical validation and utility of ctDNA-based molecular residual disease (MRD). The group has begun by defining the specific clinical applications of MRD testing across the patient journey, with a focus on clinical study design elements needed to validate these use cases. Following a comprehensive review of the state of the field the group will initially choose one application on which to focus, with others to follow in future steps. This process will yield a comprehensive overview of the MRD landscape, potential applications, and guidelines to achieve clinical validation. Following FDA feedback, these insights will be captured in a white paper publication with the aim of accelerating adoption of MRD testing as a key element for optimizing patient management.  

The primary objective of the Recommended Data Element (RDE) working groups are to provide and communicate clear justification and validation for the minimal technical data elements (MTDEs) that have been developed by the BLOODPAC Consortium, recommended for collection and submission of data to the BLOODPAC Data Commons (BPDC).

• Clinical and Patient Context Variables– Christina Lockwood (Association for Molecular Pathology) & Jason Merker (American Society of Clinical Oncology)

  The goal of the Clinical & Patient Context Variables working group is to identify, develop and build consensus around minimal and measurable Clinical Context and Patient Context Variable Data Elements recommended for collection and submission of data to the BPDC. The lists will focus on identifying patient and disease factors that may affect assay results at the time the biospecimen is acquired. These Minimal Technical Data Elements (MTDEs) ensure data submitted to the BPDC can be accurately evaluated and analyzed by BLOODPAC participants and members of the broader liquid biopsy community.

• Molecular Residual Disease/Multi-Cancer Early Detection RDE— Greg Jones (NeoGenomics/Inivata)

  The molecular residual disease and early detection & screening (MDS/EDS) RDE working group is applying the lens of MRD and EDS testing to BLOODPAC’s existing work on minimal technical data elements (MTDEs) for liquid biopsy data reporting. This team is first developing a list of MRD- and EDS-specific pre-analytical MTDEs, and will next work on assembling analytical, patient and clinical variables. The MRD/EDS RDE working group is closely aligned with the umbrella MRD and EDS working groups and their lexicon projects, to ensure that a controlled vocabulary is used throughout the publications that result from these efforts.

• Pre-Analytical Variable— Philip Febbo (Illumina), Anne-Marie Martin (GSK), Howard Scher (Memorial Sloan Kettering Cancer Center)

  The Pre-Analytical Variable working group has developed a list of 11 Pre-analytical Minimal Technical Data Elements (MTDEs), attributes recommended for collection and submission of data to the BPDC. These MTDEs ensure data submitted to the BPDC can be accurately evaluated and analyzed across BLOODPAC participants and members of the broader liquid biopsy community.

• Landscape Analysis– Christina Lockwood (Association for Molecular Pathology) & Jason Merker (American Society of Clinical Oncology)

  The Pre-Analytical Variable Landscape Analysis working group is authoring a review of the pre-analytical variables recommended for data collection. The goal of this Landscape Analysis is to better understand and promote harmonization of minimal standards for data collection in the liquid biopsy field. The working group includes representation from a variety of organizations, including CAP, ASCO, NCI, ISBER, ESMO, ISO, CLSI, and AMP.

The Data Science working group provides a secure and compliant data commons to store, harmonize and analyze liquid biopsy data submitted by member organizations, with the goal of sharing this data with the larger liquid biopsy, translational and scientific communities. This working group maintains compliance with existing standards (FASTQ, BAM and VCF) and develops new standards and protocols for formatting and integrating data specific to liquid biopsy outputs.

The Reimbursement & Policy working group (RWG) was formed among a diverse group of market access, health economics and regulatory staff. The working group first acquired a baseline understanding of payer perceptions of liquid biopsy’s role in therapy selection and monitoring applications. This baseline informed a roadmap to address coverage gaps for liquid biopsy through “above brand” evidence-based payer education. The working group speaks with one voice across all payer policymakers, and develops a new framework for them to assess utility of liquid biopsy assays and health economic value. Success is measured by improvements in patient access and outcome, made possible by expanding payer coverage, coding, and payment for these medically necessary tests.

To achieve the group’s goals, the team focuses on three different areas: 

• Member Education — Maude Champagne (Illumina)

  There is significant diversity in the work being done by BLOODPAC members. This subgroup ensures that coverage and policy changes are shared with the broader reimbursement and policy team. It creates a space for sharing best practices and mobilizing across industries to increase liquid biopsy access.

• Advocacy — Robert Dumanois (Thermo Fisher Scientific)

  The focus of the subgroup is to generate comment letters on topics related to the use of liquid biopsy in the clinical setting. This includes public comments on CMS topics, including NCDs and LCDs, commercial payer medical policy issues, professional guidelines, and other ad hoc topics identified by the reimbursement working group. Examples of recent correspondence may be seen here.

• Risk Holder Engagement — Suzanne Belinson (Tempus) & Trish Brown (CVS/Aetna)

  This subgroup aims to educate payers, laboratory benefit managers and other risk holders on the evidence-based clinical utility, economic value and patient benefit of liquid biopsy. Working collaboratively with risk holders to align incentives and develop evidence frameworks is also primary to the mission of this group.

The focus of the Accessibility working group is to identify key barriers to clinical use and equitable access to liquid biopsy tests, address disparities, and democratize the use of this technology. The working group recently published a report on accessibility challenges and proposed solutions. Read the article here.

Next, they will work on developing educational content for providers and patients on liquid biopsy technology and clinical applications, for dissemination by member organizations. Ultimately, the aim of this group is to ensure that the next decade will bring utilization of this novel precision medicine technology to improve outcomes in all communities.

The Global Regulatory working group was founded to address the opportunity for international regulatory standards for diagnostic testing with liquid biopsy. The goal of the group is to facilitate the harmonization of guidelines and expectations for review of liquid biopsy technologies to enable rapid regulatory approval for patient benefit. In the short term, members are working to establish a global regulatory partnership and obtain input on current BLOODPAC deliverables. In the long term, the working group will facilitate the development of additional deliverables with input from global regulatory agencies.