NIDDK Laboratory Working Group Virtual Annual Meeting - October 28, 2024

Welcome and Introductions
Greg Miller, Virginia Commonwealth University (VCU)
Jesse Seegmiller, University of Minnesota Medical School

Dr. Greg Miller, Chair of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Laboratory Working Group (LWG), welcomed the participants to the meeting and asked them to introduce themselves.

The LWG was formed in 2003, with the aim of standardizing the serum creatinine measurement used to determine estimated glomerular filtration rates (eGFRs), which was accomplished by 2010. Subsequently, the LWG began working to standardize urine albumin (UA) measurements and reporting. Dr. Miller explained that the joint NIDDK/International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) LWG for standardization of UA measurement was convened to formally assess the current state of agreement among measurement procedures, assist in the development of reference measurement procedures (RMPs) and reference materials (RMs), evaluate the commutability characteristics of RMs, and evaluate the ability to use reference systems to standardize routine measurement procedures. The aims for today’s meeting were to review the development of reference system components and to determine the timeline for implementing standardization of UA measurements.

Summary of Current Resources for Standardization of Urine Albumin in vitro Diagnostic Medical Devices
Greg Miller, VCU

Dr. Miller provided an overview of the current certified reference materials (CRMs) and RMPs for UA measurements.

Some CRMs for UA are pure albumin intended for the calibration of liquid chromatography (LC)/mass spectrometry (MS) measurement procedures. Dr. Miller described SRM 2925, a frozen recombinant human serum albumin solution developed by the National Institute of Standards and Technology (NIST) and used as a primary reference calibrator for UA. Additionally, National Metrology Institute of Japan (NMIJ) developed CRM 6202-a, composed of purified human serum albumin in an aqueous solution. Both CRMs are available for use and listed in the Joint Committee for Traceability in Laboratory Medicine (JCTLM) Database for Reference Material.

Some CRMs for UA are used as secondary commutable calibrators for end-user in vitro diagnostic (IVD) measurement procedures. NIST developed SRM 3666, which is composed of frozen human urine with values assigned for endogenous albumin, creatinine, and albumin-to-creatinine ratio (ACR). A complete report on the characterization of the material has been published. The purpose of SRM 3666 is to support the accuracy and global comparability of clinical measurement procedure UA results. Four concentration levels of SRM 3666 are available, with approximate concentrations of 8 mg/L, 31 mg/L, 113 mg/L, and 360 mg/L. The commutability assessment of SRM 3666 is in progress with participating IVD platforms: Abbott Alinity, Beckman-Coulter AU, Mindray BS-800M, Quidel Ortho Vitros 5600, Roche Cobas c503, and Siemens Atellica which represent more than 80 percent of the market in the United States, Europe, and Asia. The commutability assessment results will be published to support JCTLM nomination in 2025, with SRM 3666 anticipated to be listed by JCTLM in 2026.

The Health Science Authority (HSA) in Singapore developed HRM-3004A, composed of frozen albumin and creatinine in human urine. Two concentration levels of HRM-3004A are available, at approximate concentrations of 40 mg/L and 226 mg/L. The commutability assessment was conducted on the following participating IVD platforms: Abbott Architect c1600, Beckman-Coulter AU5800, Roche Cobas c311 and c702, and Siemens Atellica CH. A complete report on the commutability of the material has been published (Liu et al., 2022). This product was nominated to JCTLM this year and is anticipated to be listed in 2025.

Dr. Miller shifted the focus to discussing the recent developments in LC/MS RMPs for UA. RMPs from NIST and HSA were both nominated to JCTLM this year. Additionally, a publication is being prepared to support JCTLM nomination in 2025 for an RMP being developed at the University of Minnesota. Mayo Clinic is in the process of optimizing calibration of an RMP under development there.

Dr. Miller reviewed a recent publication from LWG in Clinical Chemistry (Miller et al., 2024) discussing the extent of equivalence of results among three candidate MS RMPs, which is part of the requirement for nominations to JCTLM. He noted two graphs showing agreement at lower values (30 mg/L to 35 mg/L) and higher values (100 mg/L to 240 mg/L) for the mean results from each RMP laboratory: Advanced Research and Diagnostic Laboratory at the University of Minnesota; HSA, using calibrators from NIST; HSA, using calibrators from NMIJ; and NIST. He reviewed a table reporting overall statistical agreement of mean results among the RMP laboratories. Dr. Miller shared the new modified goals for analytical performance specifications for clinical laboratory analyzers to accommodate the uncertainty contribution from variability in results from the different RMP laboratories. The desirable goal is for bias between a clinical laboratory analyzer and an RMP to be ≤ 9%, with an optimal goal of ≤ 3%. The quality control (QC) samples measured at each RMP laboratory were the 2 levels of CRM from HSA. QC results were within the uncertainty of the values assigned to the CRMs providing supporting evidence that the agreement among the laboratories is acceptable.

Two Options for Metrological Traceability of Urine Albumin Results to the International System of Units
Greg Miller, VCU

Dr. Miller discussed two options for metrological traceability of UA results in International Organization for Standardization (ISO) 17511: (1) splitting clinical urine samples with an RMP laboratory and (2) using a urine matrix–based CRM as a secondary calibrator for the manufacturer’s selected measurement procedure.

Dr. Miller shared a diagram of the metrological traceability hierarchy for the calibration of UA measurement procedures. One option for standardizing calibration of current IVD medical devices for urine albumin calibration is to split clinical samples with an RMP laboratory, and use the clinical samples as calibrators for the manufacturer’s selected measurement procedure. As discussed previously, JCTLM listings of the NIST and HSA RMPs are anticipated to be available in 2025 and the Minnesota RMP in 2026. The process for acquiring and assigning values to clinical samples by a RMP is expensive.

Another more cost-effective option for traceability to SI uses commutable secondary CRMs in the existing calibration hierarchies of manufacturers. The JCTLM listings for HSA CRM HRM-3004A is expected to be available in 2025 and NIST SRM 3666 in 2026. NIST 3666 will be suitable for use following the completion of the commutability assessment in 2025.

Coordination with the U.S. Food and Drug Administration for Standardizing Calibration of IVD Medical Devices for Urine Albumin
Uyen Chu, U.S. Food and Drug Administration (FDA)

Dr. Uyen Chu, a scientific reviewer at the FDA Center for Devices and Radiological Health (CDRH), provided a historical review of the standardization of creatinine assays from 2006 to 2008, indicating that a similar process may be applicable for UA standardization. From 2006 to 2008, creatinine assays were submitted to the FDA for review under a special 510(k) that provided for a decision within 30 days rather than the 90 days that FDA has to complete the review for a standard 510(k). The caveat that accompanies the special 510(k) is that the timeline may be prolonged if major deficiencies in the assay are prevalent. However, manufacturers can develop a risk assessment based on changes to the test system when UA RMs become available to determine the types of studies that are needed for FDA submission. Dr. Chu explained an additional option for accelerated review of high-quality submissions under the FDA’s traditional 510(k). The Office of In Vitro Diagnostics triage program can expedite the review process, and a decision can be made within 30 days.

Dr. Chu concluded with recommendations for the LWG. She encouraged manufacturers to engage with the FDA and utilize the pre-submission process to seek feedback before submitting assays. Dr. Chu also recommended developing a risk assessment based on potential changes resulting from the standardization of UA clinical measurement procedures.

Planning Timeline for the IVD Manufacturers to Initiate the Urine Albumin Standardization Program
Greg Miller, VCU

Dr. Miller shared the anticipated timeline for IVD manufacturers to initiate the UA standardization program. He noted that manufacturers should maintain the current UA calibration hierarchies for the time being and make plans for implementing the NIDDK LWG/IFCC Working Group for Standardization of Albumin Assay in Urine (WG-SAU) higher-order reference system when it becomes available.

The following tasks remain to establish standardization of UA:

• IVD manufacturers will recalibrate clinical laboratory measurement procedures to the new higher-order references.
• IVD manufacturers will coordinate and introduce new calibration traceability for clinical laboratory measurement procedures over an agreed time interval.
  • Dr. Miller suggested that the LWG and IVD manufacturers synchronize their efforts over a period of 6 to 12 months.
• A substantial education program will be developed to inform clinical laboratories and care providers of the transition to standardized urine albumin and uACR measurements.
  • Adopting standardized clinical laboratory measurement procedures will resolve inconsistencies when applying current clinical guidelines and produce in more effective and consistent patient care.

Dr. Miller began a discussion with the IVD manufacturers to establish a feasible timeline for transitioning their calibration system to the new SI-traceable process and introducing it to the commercial landscape.

Discussion

• Dr. Achim Grebe commented that Roche Diagnostics has begun to plan and is currently awaiting input from their internal regulatory affairs team.
• The participants agreed that 2027 is a realistic target for transitioning to standardized calibration, considering the global applications, internal processes, regulatory processes, and magnitude of adjustments for IVD manufacturers.
• Dr. David Seccombe inquired about implementing a certification program, operated under a central laboratory, to document and substantiate traceability in the marketplace. Dr. Miller explained that such infrastructure was currently not under consideration. However, the secondary CRMs may serve as the mechanism to achieve global standardization.
• Dr. Paula Caposino inquired whether the working group was also considering semiquantitative methods typically used at Clinical Laboratory Improvement Amendments–waived sites or methods used at non-waived POC sites. Dr. Miller responded that the LWG program is oriented around mainframe laboratory analyzers but that point-of-care quantitative devices are expected to undergo the same calibration transition to standardize results. Although the focus of the LWG has been on mainframe clinical laboratory procedures, point-of-care devices have naturally followed because consistent standards are needed for both. Thus, although the global approach includes point-of-care devices, a targeted approach needs to be developed to address this segment of the manufacturing industry.
• Dr. Caposino followed up about the feasibility of calibrating semiquantitative methods, like urine dipstick tests, and asked if these methods had been considered from a technical standpoint. Dr. Miller explained that typical urine dipstick tests have not been a focus of the LWG and IFCC, but that point-of-care devices that provide quantitative results for UA may be more appropriate for inclusion.
• Dr. Caposino highlighted the prevalence, accessibility, and low cost of dipstick technologies. She also suggested considering ways to differentiate restandardized assays from assays that have not been restandardized, possibly through rebranding. She also expressed interest in further information on mainframe instruments and the regulatory classification of these laboratory-based methods, such as the 510(k) numbers, for these types of devices which, if Class I and indicated for laboratory use, would be exempt from FDA review. Dr. Miller agreed with the suggestion of distinguishing standardized and nonstandardized assays and added that educational initiatives could address the topic.
• Dr. Miller emphasized the importance of coordinating with IVD manufacturers to ensure that the new recalibrated products are introduced to the market in a synchronized period of 12 months as agreed for 2027. He also stressed educating stakeholders about the upcoming changes and traceability expectations, and suggested that collaborators use the next two years to prepare for full implementation in 2027. Dr. Miller stated that a long-term approach allows IVD manufacturers and other stakeholders to adapt to new expectations and ensures a smooth transition to standardized traceability practices.
• Dr. Caposino raised the issue of traceability in assay documentation, noting that clear traceability information is often difficult or not described in package inserts and recommending that traceability information be made more accessible. She emphasized the importance of standardized methods, even if regulatory bodies may not have the authority to mandate changes outright. Dr. Miller called attention to the success of the creatinine standardization program that used isotope dilution mass spectrometry (IDMS)–traceable to designate assays that had recalibrated to standardize creatinine. The structured approach for designating traceability was easily understood and helped to clarify expectations across the industry. He suggested adopting IDMS traceability for UA to clearly designate assays that were standardized.
• Dr. Caposino discussed the challenges in promoting traceability in assays and devices. Although the FDA reviews traceability claims, changes typically cannot be mandated. She suggested encouraging manufacturers—including those producing semi-quantitative and quantitative point-of-care-devices to participate in the restandardization efforts with the goal to expand access to these restandardized devices.
• Dr. Seccombe returned to the subject of certification for traceability, noting that RMP laboratories could provide a basic framework. He suggested that a certification program would encourage compliance within the commercial landscape because it would create pressure on manufacturers to meet traceability standards. Such a program could be structured to accelerate the adoption of traceability. Dr. Afshin Parsa, NIDDK, supported the idea of IDMS traceability for UA, which was well received in past programs. He highlighted that emphasizing IDMS traceability also creates pressure within the research community, apart from formal certification. Dr. Jenna Norton, NIDDK, acknowledged that although a certification program may be useful, it falls outside the direct scope of the National Institutes of Health, and she suggested collaborating with other agencies to consider the feasibility and potential impact of a certification-based approach to traceability. Meeting participants were supportive of a certification-based approach to traceability.
• Dr. Norton raised the issue of eGFR reporting and the potential need for a more standardized approach to eGFR reporting that more accurately reflects clinical standards. In particular, reporting an eGFR above 60 as “normal” may not always be accurate. Dr. Miller agreed and highlighted that the National Kidney Foundation Laboratory Engagement Initiative is pushing for more accurate reporting of eGFR. He mentioned potential collaborations with the College of American Pathologists, which plans to survey participants on GFR reporting in an upcoming PT survey. The goal is to ensure that reporting practices are updated to reflect current clinical understanding.

Summary and Follow-Up Items
Greg Miller, VCU

Dr. Miller reviewed the key next steps:

• Schedule meetings with the FDA and IVD manufacturers to discuss coordinating submissions (as needed) and FDA review of the recalibrated urine albumin IVD medical devices (as needed).
• Engage with regulatory agencies in other countries.
• Develop steps to implement recalibrated clinical laboratory measurement procedures in 2027 in collaboration with IVD manufacturers.
• Develop educational programs to inform all stakeholders.

Adjournment

Dr. Miller thanked the participants for attending and adjourned the meeting at 10:55 a.m. EDT.

Lorin Bachmann, Ph.D., DABCC
Chair, International Federation of Clinical Chemistry Working Group for Standardization of Albumin in Urine
Associate Professor, Department of Pathology
Co-Director, Clinical Chemistry Laboratory
Virginia Commonwealth University
lorin.bachmann@vcuhealth.org

Ashley Beasley-Green, Ph.D.
Staff Scientist, Biomolecular Measurement Division
National Institute of Standards and Technology
ashley.beasley@nist.gov

Johanna Camara, Ph.D.
Research Chemist
National Institute of Standards and Technology
johanna.camara@nist.gov

Paula Caposino, Ph.D.
Deputy Division Director, Division of Chemistry and Toxicology Devices
Center for Devices and Radiological Health
U.S. Food and Drug Administration
paula.caposino@fda.hhs.gov

Uyen Chu, Ph.D.
Scientific Reviewer, Center for Devices and Radiological Health
U.S. Food and Drug Administration
uyen.chu@fda.hhs.gov

Jian Dai, Ph.D., FAACC, FCACB
Director
Mindray
j.dai@mindray.com

Joris Delanghe, Ph.D.
Professor, Department of Clinical Chemistry
University Hospital Ghent
joris.delanghe@ugent.be

James Fleming, Ph.D., FACB
Vice President and Director, Scientific Affairs
Laboratory Corporation of America
jim_fleming@labcorp.com

Achim Grebe
Roche Diagnostics
achim.grebe@roche.com

Anders Grubb, M.D., Ph.D.
Professor of Clinical Chemistry
Lund University
anders.grubb@med.lu.se

Qinde Liu, Ph.D.
Consultant Scientist
Health Sciences Authority, Singapore
liu_qinde@has.gov.sg

Greg Miller, Ph.D.
Chair, Laboratory Working Group
Professor, Department of Pathology
Co-Director, Clinical Chemistry Laboratory
Director, Pathology Information Systems
Virginia Commonwealth University
greg.miller@vcuhealth.org

Jenna Norton, Ph.D., M.P.H.
Program Director
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
jenna.norton@nih.gov

Afshin Parsa, M.D., M.P.H.
Program Director
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
afshin.parsa@nih.gov

Karen Phinney, Ph.D.
Group Leader, Biomolecular Measurement Division
National Institute of Standards and Technology
karen.phinney@nist.gov

David W. Seccombe, M.D., Ph.D., FRCPC
Managing Director
Canadian External Quality Assessment Laboratory
dseccombe@ceqal.com

Jesse Seegmiller, Ph.D.
Associate Professor, Department of Laboratory Medicine and Pathology
University of Minnesota Medical School
jseegmil@umn.edu

Robert Star, M.D.
Director, Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
robert.star@nih.gov

Tang Lin Teo, Ph.D.
Division Director
Health Sciences Authority, Singapore
tang_lin@has.gov.sg