Clinical Validation of a Candidate Biomarker for Neurological Disease (U44 Clinical Trial Optional)
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The official link for this solicitation is: https://grants.nih.gov/grants/guide/pa-files/PAR-18-548.html
Application Due Date:
Available Funding Topics
Clinical Validation of a Candidate Biomarker for Neurological Disease (U44 Clinical Trial Optional)
The overarching purpose of this Funding Opportunity Announcement (FOA) is to fill critical scientific gaps needed to advance strong candidate biomarkers from discovery to clinical use. Specifically, the focus of this FOA is to support the clinical validation of candidate biomarkers of neurological disease using retrospective and/or prospective methods. Research supported by this FOA should demonstrate that biomarker change is reliably correlated with variables such as clinical outcome, disease progression, disease onset and severity, drug target engagement or response to a drug. In addition, biomarker response should be specific to the disease or therapeutic as demonstrated at multiple clinical sites.
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 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 III 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 retrospective and/or perspective clinical validation that can be used to evaluate the biomarker for clinical utility (for use in clinical trials or clinical practice). This funding opportunity uses a cooperative agreement mechanism that enables significant input from NIH staff to assist investigators with the design and implementation of studies focused on clinical validation and/or evaluation of the biomarker for use in clinical practice.
Applications to this FOA must propose to conduct retrospective and/or perspective clinical validation studies of a candidate biomarker.
The definitions of the terms context of use, analytical validation, clinical validation and clinical utility are provided below for the purposes of this FOA:
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
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 measurements technical performance, but does not validate the usefulness of the measurement.
Clinical Validation: Establishing that the biomarker acceptably identifies, measures or predicts the concept of interest.
Clinical Utility: The conclusion that a given use of a biomarker will lead to a net improvement in health outcome or provide useful information about diagnosis, treatment, management or prevention of a disease. Clinical utility includes the range of possible benefits or risks to individuals and populations.
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.
- Applicants should have an identified biomarker with a working hypothesis regarding context of use. 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.
- Analytical validation for the candidate biomarker should be completed and consistent with FDA standards for accuracy, precision, analytical sensitivity/specificity, effects of interfering substances, dynamic range, establishment of appropriate quality control, and harmonization of analytical performance within the context of use for the biomarker. Supporting data providing evidence for this assertion should be provided. It is recognized that some optimization may be required as the process of clinical validation evolves.
- Preliminary Data: Applications should include preliminary validation data demonstrating that the candidate biomarker identifies, measures or predicts the concept of interest.
- 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.
- Strong justification for further development of the biomarker as well as proven ability of the investigative team to conduct retrospective and/or prospective studies examining the clinical utility of the biomarker is important.
- The current status of the biomarker and its assay (i.e., data on analytical and early preclinical and/or clinical validation) is a critically important component of the application.
- The studies supported through this FOA should be focused on clinical validation of a biomarker, which may or may not involve administration of a therapeutic entity. Examples of biomarkers that could involve administration of a therapeutic entity include pharmacodynamic, predictive, monitoring and safety biomarkers. Other types of biomarkers, such as diagnostic, prognostic and risk/stratification biomarkers may not involve such intervention. This FOA does not support clinical studies focused on the evaluation of efficacy or safety.
- Metrics for clinical validation milestones will be used to assess annual progress throughout the duration of the funding period.
- This FOA is intended to support clinical studies aimed at verifying that biomarkers are suitable for use in multi-site clinical trials.
- Appropriate statistical analyses should be based on the primary clinical outcome. Primary clinical outcomes can be characterized as: 1) a binary event such as having a disease or not having a disease, 2) a time to event outcome such as time to diagnosis and 3) a quantitative or continuous outcome such as change in a numerical biomarker of disease progression.
Analytical Validation can include the following metrics with use of FDA guidance standards appropriate for the context of use:
- 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.
Clinical Validation can include the following metrics with use of FDA guidance standards appropriate for the context of use:
- Demonstration of association of the result of the biomarker assay with a clinical endpoint (e.g., survival, response, disease presence or absence) in samples or data from patients that have been exposed to a uniform intervention or that have or will develop a disease or disorder
- Definition of the sensitivity and specificity of the assay result within the context of the defined clinical endpoint and clinical population
- Estimation of the prevalence of the marker within subjects or patients for the intended clinical context
- Establishment of an appropriate cut-off or threshold for the assay using appropriate statistical analysis
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.
Qualification of Biomarkers: If biomarker qualification is the intent of the application, applicants are encouraged to collect the clinical data needed to apply to the FDA for qualification of biomarkers intended to be used in the regulatory review process. Researchers are encouraged to initiate the qualification process with the FDA prior to submitting an application to this FOA (if biomarker qualification is the intent of the proposal). A plan to obtain advice from the FDA on the development of the biomarker should be included in the application, if applicable. The FDA provides additional information about the Drug Development Tools Biomarker Qualification Program on its website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm.
Examples of clinical validation studies intended to be supported through this FOA include, but are not limited to the following:
- Clinical validation studies of the biomarker, with the goal of establishing robust correlations between biomarker and disease or therapeutic response
- Optimization of analytical validation for the purposes of increasing feasibility in multiple clinical studies and sites
- Expanded determination of context of use, using FDA guidelines
- Retrospective, well controlled, multi-site clinical studies using meta-analysis or multiple independent studies
- Prospective focused and randomized multi-site clinical studies
- Studies aimed at demonstrating that candidate biomarkers are fit for use in specific contexts relevant to multi-site clinical trials
- Studies to characterize patient cohorts with biomarkers that will be used to stratify patients or determine inclusion/exclusion criteria in clinical trials
- Intervention studies where pharmacodynamic, predictive, monitoring, or safety biomarker validation is the focus of the study
- Non-intervention studies where diagnostic, prognostic and risk/stratification biomarker validation is the focus of the study
- Studies designed to assess the health impact of a biomarker in clinical practice
- Studies designed to provide a data package suitable for FDA biomarker qualification
Examples of clinical validation studies that are considered not appropriate for this FOA include, but are not limited to the following:
- Natural history studies aimed at exploring disease pathophysiology, genetic or epigenetic mechanisms
- Applications that propose any animal studies
- Studies of biomarker identification or technology development
- Biomarker analytical validation as the sole intent (it is recognized that optimization of the method of detection may continue throughout the clinical validation process)
- Applications that propose only to create or maintain patient registries
- Clinical testing of candidate therapeutics
- Clinical intervention studies other than those necessary to validate biomarkers (see NINDS statement below)
- Applications that request support for infrastructure to establish new clinical trial networks are beyond the scope of this FOA.
NINDS supports the clinical validation of biomarkers that indicate pharmacodynamic responses to therapeutics, 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 of biomarker discovery should seek funding through the parent FOAs for research project grants.
Studies of biomarker analytical validation should seek funding through the companion FOA, "Analytical Validation of a Candidate Biomarker for Neurological Disease (U44 - Clinical Trial Optional)" PAR-18-549
Prospective applicants are encouraged to discuss project suitability for this FOA with the NINDS Scientific/Research Contact listed in the Agency Contacts section below.
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 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 clinical validation and biomarker qualification, including statistical design and analysis experts.
Leveraging Existing Research Resources
Applicants should leverage existing research resources for their studies. An example of such an existing resource is the NINDS BioSEND https://pdbp.ninds.nih.gov/biorepository or other existing biospecimen, imaging and 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.
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 regarding the metrics for clinical validation of the biomarker (e.g., demonstration of the association of the result of the assay with a clinical endpoint, definition of sensitivity and specificity of the biomarker, estimation of the prevalence of the biomarker, establishment of an appropriate cut-off or threshold for the biomarker, etc.). Submission to the FDA of a full qualification package could be among the milestones. For further information, see:
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.