Accomplishments

2020 Biomarkers Consortium Accomplishments

Advancing Therapeutics

1. The 21st Century Cures (Cures Act) has been updated with newly published Final Guidance for Qualification of Drug Development and Tools (DDT) that will act as an essential tool and roadmap for industry and all BC projects moving forward – Qualification Process for Drug Development Tools Guidance for Industry and FDA Staff (see section 507)
2. The BC’s Remote Digital Monitoring for Medical Product Development Workshop held in February 2020 resulted in key considerations and recommendations which were incorporated in FDA’s newly launched Innovative Science and Technology Approaches for New Drugs (ISTAND) pilot program to support use of novel drug development tools. 

FDA Biomarker Qualification Milestones

Letter of Intent (LOI) Submissions

• Vol-PACT Phase II: Advanced metrics and modeling with Volumetric CT for Precision Analysis of Clinical Trial results – 

LOI Approvals

• PROGRESS OA: Clinical Evaluation and Qualification of Osteoarthritis Biomarkers – (2) Biochemical markers (urine or urine/serum) and radiographic measure of trabecular bone texture (TBT) as prognostic enrichment molecular biomarkers for use in phase 2 and 3 clinical trials
• Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE) – Circulating biomarkers for diagnosis of patients likely to have liver histopathologic findings in Non-Alcoholic Steatohepatitis (NASH)
• The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) – Oculomotor Index of Gaze to Human Faces as a diagnostic biomarker to select a less heterogeneous subgroup within subjects with autism spectrum disorder (ASD) for clinical trial enrichment

Qualification Package Submissions

• PROGRESS OA: Clinical Evaluation and Qualification of Osteoarthritis Biomarkers - Prognostic enrichment imaging biomarker panel for use in phase 2 and 3 clinical trials for patients with a diagnosis of knee osteoarthritis and likely to experience long-term disease progression
•  Study to Advance Bone Mineral Density as a Regulatory Endpoint (SABRE) (Bone Quality) – Qualification of change in bone mineral density as measured by Dexa imaging as a surrogate endpoint for fracture in osteoporosis. 

Consensus Statements and Impact on Regulatory Decisions

• The International Liquid Biopsy Standardization Alliance (ILSA) Collaborative Community Charter submitted to FDA - focused on promoting the global use of liquid biopsy and common reference standards in oncology and beyond published a Charter White Paper in Science Direct - https://www.sciencedirect.com/science/article/pii/S1040842820302481

Scientific Publications

• 3 publications for the Biomarkers Consortium on Remote Digital Monitoring for Medical Product Development
• 2 publications for the Advanced metrics and modeling with Volumetric CT for Precision Analysis of Clinical Trial results (Vol-PACT Phase II) Project
• 1 publication for the Bone Quality Project
• 2 publication for the Osteoarthritis Biomarkers Project
• 7 publications for the Sarcopenia as a Valid Biomarker for Identifying Individuals at Risk of Disability Project

Newly Launched Projects in 2020

• The Validation of Plasma Aβ as a Predictor of Amyloid Positivity in Alzheimer's Disease Project in March 2020 
•  The Chemotherapeutic Impact on the Immune MicroEnvironment (ChIIME) Project in February 2020
• The NiP-Metastatic Prostate Cancer Project in November 2020

2019 Biomarkers Consortium Accomplishments

Advancing Therapeutics

• Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infections (CABP/ABSSSI) Project – Xenleta (lefamulin) – new approval of project partner (Nabriva) antibiotic
• Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infections (CABP/ABSSSI) Project – Baxdela (delafloxacin) – expanded label of project partner (Melinta) antibiotic
• Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia Clinical Endpoint Development (HABP/VABP) – expanded label of Zerbaxa (ceftolozane/tazobactam)

FDA Biomarker Qualification Milestones

Letter of Intent (LOI) Submissions:

• Clinical Evaluation and Qualification of Osteoarthritis Biomarkers (PROGRESS OA) Project – Biochemical Markers (Urine or urine/serum) as prognostic enrichment molecular (urine and serum) biomarkers for use in phase 2 and 3 clinical trials
• Clinical Evaluation and Qualification of Osteoarthritis Biomarkers (PROGRESS OA) Project – Radiographic measure of trabecular bone texture (TBT) as prognostic enrichment imaging biomarker panel for use in phase 2 and 3 clinical trials
• Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE) Project – Circulating Biomarkers for Diagnosis of Non-Alcoholic Steatohepatitis (NASH) 

LOI Approval: 

• Clinical Evaluation and Qualification of Osteoarthritis Biomarkers (PROGRESS OA) Project – Approved to move forward to a qualification plan (May 9, 2019) to qualify an Imaging LOI, Legacy biomarker LOI conversion submission in Q4 2018
• Autism Biomarkers Consortium for Clinical Trials (ABC-CT) – Approved to move forward to a qualification plan (May 6, 2019). This plan would qualify an electroencephalogram (EEG) measure of neural response to human faces as a diagnostic enrichment biomarker to identify a homogenous subgroup of persons with ASD for clinical trials.
• Vol-PACT Phase II: Advanced metrics and modeling with Volumetric CT for Precision Analysis of Clinical Trial results – Approval to move forward to qualification plan (Feb. 19, 2019) for assessment of tumor volume change as measured by volumetric computed tomography as a pharmacodynamic biomarker for new oncologic drug clinical trial therapy of solid tumors.

Qualification Plan Submissions:

• Clinical Evaluation and Qualification of Translational Kidney Safety Biomarkers (Kidney Safety) Project – Safety biomarker panel to be used in conjunction with three conventional kidney biomarkers (sCr, BUN, and sCysC) to indicate potential drug-induced injury to the renal tubule in individuals with normal renal function enrolled in early phase drug development clinical trials 
• Study to Advance Bone Mineral Density as a Regulatory Endpoint (SABRE) (Bone Quality) Project – Qualification of change in bone mineral density as measured by Dexa imaging as a surrogate endpoint for fracture in osteoporosis. 

Consensus Statements and Impact on Regulatory Decisions 

Sarcopenia 2 project released evidence-based disease diagnosis criteria - J Gerontol A Biol Sci Med Sci. 2019 Mar 14. pii: glz081. doi: 10.1093/gerona/glz081

Drug Development Clinical Tools

The FNIH Biomarkers Consortium Kidney Safety Biomarker Project Team and the Critical Path Institute’s Predictive Safety Testing Consortium’s Nephrotoxicity Working Group authored a comprehensive User's Guide: Kidney Safety Composite Measure Biomarker for Use in Clinical Development (May 15, 2019) that describes and outlines the use of the qualified composite measure biomarker for use in Phase 1 clinical trials

Scientific Publications

• 2 publications for the Biomarkers Consortium

  • The Foundation for the National Institutes of Health Biomarkers Consortium: Past Accomplishments and New Strategic Direction. Menetski J, Hoffmann S, Cush S, Kamphaus T, Austin C, Herrling P, Wagner J. Clinical Pharmacology & Therapeutics Volume 105(4). 2019 April.
  • The FNIH Biomarkers Consortium Embraces the BEST. Menetski J, Austin CP, Brady LS, Eakin G, Leptak C, Meltzer A, Wagner JA. Nat Rev Drug Discov. 2019 Jul;18(8):567-568. doi: 10.1038/d41573-019-00015-w.
• 2 publications for the Osteoarthritis Biomarkers Project
• 1 publication for the Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia Clinical Endpoint Development (HABP/VABP) Project
• 1 publication for the Bone Quality Project
• 1 publication for the Sarcopenia as a Valid Biomarker for Identifying Individuals at Risk of Disability Project
• 1 manuscript for the High Definition Single Cell Analysis of Blood and Tissue Biopsies in Patients with Colorectal Cancer Undergoing Hepatic Metastasectomy Project
• 1 publication for the Treatments Against RA and Effect on FDG PET-CT (TARGET Biomarker Study) Project

2018 Biomarkers Consortium Accomplishments

 Advancing Therapeutics

• Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infections (CABP/ABSSSI) Project - Tigecycline (expanded label)
• Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia (HABP/VABP) Project - Ceftazidime/Avibactam (AVYCAZ) 
• Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and MoLecular Analysis (I-SPY TRIAL 2) Project - Pembrolizumab (1st drug graduated to randomized testing in breast cancer) 

FDA Biomarker Qualification Milestones 

• Leter of Intent (LOI) Submission (1st Step in Biomarker Qualification Process): The project team submitted a biomarker description to the FDA for review as a project to be accepted into the qualification process.
  • Advanced Metrics and Modeling with Volumetric CT for Precision Analysis of Clinical Trial Results (Vol-PACT Phase II) Project − Legacy biomarker LOI conversion submission in Q4 2018
  • Autism Biomarkers Consortium for Clinical Trials (ABC-CT) Project - Biomarker LOI submission in Q4 2018 for N170, an electrophysiological biomarker linked to event-related potential from faces 
  • Clinical Evaluation and Qualification of Osteoarthritis Biomarkers (PROGRESS OA) Project - Legacy OA Imaging LOI, Legacy biomarker LOI conversion submission in Q4 2018
  • Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) Lung and Lymphoma Trials − Legacy biomarker LOI conversion submission in Q3 2018.
• LOI Approval: The FDA accepted the proposed biomarker into the qualification process.
  • Bone Quality Project - LOI approved to move forward to a qualification plan (October 16, 2018) to qualify an imaging measurement of bone mineral density as a surrogate to fracture in osteoporosis clinical trials 
• New Tool Qualified (Final Step in Biomarker Qualification Process): The FDA is confident in making regulatory decisions about drug safety using this tool.
  • Clinical Evaluation and Qualification of Translational Kidney Safety Biomarkers (Kidney Safety) Project. First ever qualification by the FDA of a clinical safety biomarker and the first qualification for the Biomarkers Consortium on July 25, 2018. Composite measure biomarker can be used to detect acute kidney injury for drugs being tested in normal volunteers in Phase 1 clinical trials. 

Consensus Statements and Impact Regulatory Decisions

• Contributions to FDA Guidance
  • FNIH/FDA Evidentiary Criteria Workshop - A whitepaper generated through the workshop contributed to the contents of the new “Biomarker Qualification: Evidentiary Framework Guidance for Industry and FDA Staff” released in December 2018 
  • HABP/VABP Project - Recommendations submitted to the FDA will be incorporated into updated 2019 Guidance 
  • OA Biomarkers Project - Contributed to the release of the “Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices, and Biological Products for Treatment, Guidance for Industry” in August 2018 
• Consensus Conference Activity
  • Sarcopenia as a Valid Biomarker for Identifying Individuals at Risk of Disability (Sarcopenia 2 Project) –– A subset of position statements defining sarcopenia and diagnosis cut-offs were voted by an international expert team on November 13, 2018. Final statements will be issued in a series of publications.

Drug Development Clinical Tools 

• Identification and Validation of Markers That Predict Long-Term Beta Cell Function and Mass (Beta Cell) Project – Established decision-making method for designing interventional clinical trials using MMTT and AST with confidence across the glucose tolerance spectrum for diabetes trials. These methods are being actively implemented by the partner companies, resulting in ~15% cost reduction and process efficiency improvements.

23 Scientific Publications 

• 7 manuscripts from FNIH OA Biomarkers Project
• 3 manuscripts from Bone Quality
• 3 manuscripts for Beta Cell
• 2 manuscripts from Antibacterial Projects CABP/ABSSSI and HABP/VABP
• 1 manuscript from the In Silico Modeling of Biomarkers of Atherosclerosis: Estimating Risk Reduction and Residual Risk from Statin Therapy project: Athersclerosis
• 1 manuscript from Comparison of Two PET Radioligands to Quantify the Peripheral Benzodiazepine Receptor Project: PBR28 Project 
• 1 manuscript from Placebo Data Analysis Project in Alzheimer's Disease/Mild Cognitive Impairment Clinical Trials
• 1 paper from the Advanced metrics and modeling with Volumetric CT for Precision Analysis of Clinical Trial results project: Vol-PACT