Analytical Validation of a Candidate Biomarker for Neurological Disease (U44 Clinical Trial Optional)

Purpose

The overarching purpose of this Funding Opportunity Announcement (FOA) is to fill critical scientific gaps needed to advance strong candidate biomarkers of neurological disease from discovery to clinical use. Specifically, the focus of this FOA is on the validation of analytical methods for biomarker measurements, including evaluation of the assay, its performance characteristics, and the optimal conditions that will generate reproducibility and accuracy consistent with FDA guidelines that are fit for the purpose of the assay. 

Background

A biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions.  Biomarker modalities are diverse, and can include genetic, protein, cellular, metabolomic, imaging, behavioral and physiologic endpoints.

Biomarkers have become recognized as critical to the discovery and development of therapeutics.  For example, they provide an early indication of therapeutic target engagement, and improve signal to noise by stratifying patients, thereby improving clinical trial design and enabling successful therapeutic development. In addition, biomarkers allow the evaluation of therapeutic intervention on disease progression or recurrence, as well as on the clinical manifestation of disease phenotype or severity. They are also being used to improve early diagnosis and therapeutic outcomes in cases where disease or disease manifestation could be significantly attenuated with treatment. Despite the active pace of discovery of novel biomarker candidates, few biomarkers progress beyond discovery to analytical validation and clinical practice, and robust, well-validated biomarkers for use in Phase II and Phase II clinical trials remain scant. Thus, there is a critical need to advance biomarkers to improve public health, particularly for disorders of the nervous system where failures to advance drugs from discovery to the market are notorious. 

This FOA is intended to address the gap in biomarker validation by encouraging rigorous analytical validation of the biomarker measurement.  This funding opportunity uses a cooperative agreement mechanism that enables significant input from NIH staff to assist investigators with preparing and evaluating their analytical validation strategy.

Research Objectives

Applications to this FOA must propose to conduct biomarker analytical validation studies in order to be supported.

The definitions of the terms assay, analytical validation, and context of use are provided below for the purposes of this FOA:

• Assay: An analytic procedure for detecting or measuring the presence, amount, state or functional activity of a biomarker.
• Analytical Validation: Establishing that the performance characteristics of a measurement are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include sample collection and standardization procedures). Although the goal of analytical validation is to ensure a rigorous clinical conclusion, the level of analytical rigor that is necessary depends upon the characteristics of the biomarker, the detection technology, the type of clinical question (exploratory/informational) or its intended use as a biomarker (diagnostic, predictive, pharmacodynamic, etc). Analytical validation establishes the measurement's technical performance, but does not validate the usefulness of the measurement.
• Context of Use (COU): A statement that fully and clearly describes the way the biomarker is to be used and the biomarker-related purpose of the use.  Considerations involved in defining the COU can include:  biomarker modality and method of detection, clinical population characteristics, unmet need for the new biomarker and type of biomarker (response prediction, stratification, prognostic, diagnostic, target engagement, etc). Context of use statements are discussed extensively in the following link: https://fnih.org/sites/default/files/final/pdf/Evidentiary%20Criteria%20Framework%20Final%20Version%20Oct%2020%202016.pdf                                   

Use of the BEST (Biomarkers, EndpointS, and Other Tools Resource) standardized biomarker definitions (https://www.ncbi.nlm.nih.gov/books/NBK338448/) is required for all studies.

Entry Criteria

• Applicants should have an identified biomarker with a working hypothesis regarding context of use.
• The method of detection for the biomarker should be developed, although it is understood that further optimization may occur during the validation process. Applications are not limited by biomarker type or modality, and may include validation of prognostic, predictive, monitoring, diagnostic, risk, or response biomarkers using molecular, physiological, behavioral or neuroimaging data.
• Plans for management of pre-analytic variables, such as standardization of biofluid or tissue sample collection, harmonization of instrumentation and image collection procedures across imaging centers, etc. must be in place.
• Biological rationale: Projects should be supported by a cogent biological rationale supporting the candidate biomarker, as well as a discussion regarding the unmet need for the candidate biomarker. The biological rationale should include rigorously obtained evidence that the candidate biomarker is an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions.
• Relevance for therapy development: Projects should address the relevance of the candidate biomarker for therapy development or clinical practice.

Project Characteristics

• The project must focus on assays where the biomarker is likely to be used as a tool in the diagnosis, treatment, or prevention of diseases that fall within the NINDS mission.
• Strong justification of the use of the proposed assay and its biomarker as well as proven ability of the investigative team to perform analytical validation and optimization of assays in their laboratories is important. 
• The status of the existing assay and the plan for its optimization in the clinical laboratory are critically important.
• Applications to this FOA should use technologies already in use or soon to be approved for use in clinical laboratories since this is not a technology development FOA.
• Applications to improve standardization or harmonization of assays among laboratories for use in clinical trials are appropriate for this FOA.
• Analytical validation in multiple testing sites is required, if applicable to the method of detection or its intended application.
• Metrics for analytical validation as milestones will be used to assess success in achieving each of the research plan's objectives.

Analytical Validation can include the following metrics with use of FDA guidance standards appropriate for the context of use:

• Accuracy
• Precision
• Analytical sensitivity
• Analytical specificity including interfering substances
• Reportable range of test results for the test system
• Reference intervals (normal values) with controls and calibrators
• Harmonization of analytical performance if the assay is to be performed in multiple laboratories
• Establishment of appropriate quality control and improvement procedures
• Any other performance characteristic required for test performance with determination of calibration and control procedures.

Applicants with assays that have already met the above criteria for analytical validation may apply directly to the companion FOA, "Clinical Validation of a Candidate Biomarker for Neurological Disease (U44 - Clinical Trial Optional)" (PAR-18-548) which addresses retrospective and/or prospective clinical validation of candidate biomarkers for use in clinical trials and/or clinical practice.

Data obtained after completion of this FOA should be appropriate for use as a component of the package required for FDA qualification of the biomarker:  https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm

Examples of biomarker validation studies that would be appropriate under this FOA include:

• Determination of the Context of Use for the biomarker
• Analytical validation of a tissue or biofluid biomarker assay or method of detection
• Analytical validation of an imaging biomarker
• Analytical validation of a physiological or behavioral biomarker
• Analytical validation of biomarkers with clinical intervention such as pharmacodynamic/response biomarkers, predictive biomarkers, safety biomarkers, or monitoring biomarkers
• Analytical validation of biomarkers without clinical intervention such as diagnostic, prognostic, or susceptibility/risk biomarkers
• Studies focused on improving standardization or harmonization of assays among laboratories for use in clinical trials
• The goal for analytical validation should be that the biomarker measurement meets FDA analytical performance criteria https://www.fda.gov/downloads/drugs/guidances/ucm368107.pdf  within the scope of the intended Context of Use.

Examples of studies that are not appropriate for this FOA

This FOA is not meant to support the discovery of biomarkers or to support trials that assess the clinical utility of a biomarker/assay. Rather, it is intended to advance candidate biomarkers to the point where their clinical utility could be assessed in retrospective and/or prospective correlational clinical studies because the method of detection has been rigorously validated.  Therefore, projects that are not appropriate for this FOA include:

• Natural history studies aimed at understanding disease pathophysiology, genetic, or epigenetic mechanisms
• Biomarker identification
• Initial development of the biomarker detection method (although it is recognized that optimization of that detection method will occur during the validation process)
• Therapeutic target identification
• Preclinical animal studies
• Development of candidate therapeutics
• Studies focused on clinical validation of a candidate biomarker

NINDS supports the analytical validation of biomarkers that indicate pharmacodynamic responses to therapeutics, that predict an efficacy or safety response to a therapeutic or that can be used to monitor a therapeutic response. While the studies outlined in an application may be defined as clinical trials, they should not seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, and/or clinical management.

Studies focused on examining biomarker clinical validation and evaluation of utility in clinical practice of biomarkers may be more appropriate for the companion FOA.  Prospective applicants are encouraged to discuss project suitability for this FOA with the NINDS Scientific/Research Contact listed in the Agency Contacts section below.

Collaborations

Multi-disciplinary collaboration among scientific investigators, assay developers, clinicians, statisticians, consultants, and clinical laboratory staff must be an integral part of the application. Projects proposed for this FOA will utilize multi-site design as applicable, and standardized data stewardship to ensure that data is reusable and accessible.

Investigators are encouraged to form collaborations with individuals knowledgeable in the FDA qualification process as well as those familiar with the process of analytical validation, including statistical design and analysis experts. 

Leveraging Existing Research Resources

Applicants should leverage existing research resources for their studies. Such resources may include tissue, cellular, or DNA samples from NINDS BioSEND https://pdbp.ninds.nih.gov/biorepository or other existing biospecimen, imaging or data repositories. Leveraging the resources and support from advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are also encouraged. Studies are also encouraged that leverage the resources of ongoing clinical trials supported through other Federal or private funds. 

Project Milestones

A project timeline including milestones is a required component of the application. Milestones are quantitative goals that can be used for go/no-go decision making throughout the funding period, and therefore should have quantitative criteria associated with them. All milestones should be useful as a measure of progress toward the overall goal of the project. A list of activities planned for each year are not considered milestones because they do not provide decision-making goals. Annual milestones will provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the Program Director(s)/Principal Investigator(s), and Program Official and Project Scientist.

The NIH Program Official will contact the applicant to discuss the proposed milestones prior to the award. The Program Official and Project Scientist will discuss with the Program Director(s)/Principal Investigator(s) any recommended changes to the research plan or suggestions from peer reviewers, and the plan will be revised as appropriate prior to the award. 

Studies should include quantitative milestones consistent with the metrics for analytical validation of the biomarker (e.g., sensitivity, reliability and responsiveness of the biomarker). 

Pre-Application Consultation

Under this Cooperative Agreement mechanism, NINDS Project Scientist will have substantial communication and involvement with researchers in decision making prior to award and during the conduct of the study to provide oversight of data and safety monitoring, ensure the timely completion of the proposed studies and to maximize the positive impact of the studies on upcoming clinical trials. 

Applicants are strongly encouraged to consult with NINDS Scientific/Research Staff early on during the planning for an application.  This early contact will provide an opportunity to discuss and clarify NINDS policies and guidelines, including the scope of project relative to the NINDS mission and intent of this FOA. These discussions also provide important information and guidance on how to develop an appropriate timeline and milestone plan, which are subject to peer review under this program.   

See Section VIII. Other Information for award authorities and regulations.