Department of Health
and Human Services (HHS)
and Human Services (HHS)
October 4, 2021
PAR-19-315 - Discovery of Biomarkers and Biomarker Signatures for Neurological and Neuromuscular Disorders (R61/R33 Clinical Trial Optional)
PAR-21-056 - Analytical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U01 Clinical Trial Optional)
PAR-21-057 - Analytical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U44 Clinical Trial Optional)
PAR-21-058 - Clinical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U01 Clinical Trial Optional)
PAR-21-059 - Clinical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U44 Clinical Trial Optional)
PAR-22-089 - Development of Biomarkers or Biomarker Signatures for Neurological and Neuromuscular Disorders (R61/R33 Clinical Trial Optional)
National Institute of Neurological Disorders and Stroke (NINDS)
NINDS is issuing this Notice of Special Interest to encourage the submission of applications focused on the development and validation of biomarkers for functional neurological disorders (FND).
FND are a complex and heterogeneous group of neuropsychiatric syndromes. They are characterized by symptoms of altered voluntary motor or sensory function and frequently have comorbid medical, neurological, and psychiatric disorders. Although patients with FND represent the second commonest category of referrals to neurology outpatient clinics after headache, management is complex and requires interdisciplinary approaches. The high prevalence of FND, the disability caused by symptoms, high cost in healthcare utilization and loss of productivity points to an important opportunity for development of effective therapeutic interventions.
This common, disabling, and costly group of conditions sits at the intersection of neurology and psychiatry. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM) the term functional is used as the primary descriptor in the term for this group of conditions, although the term conversion disorder is still accepted as an alternative expression that acknowledges unconscious processes in patients. However, this term emphasizes the implicit inference of causative psychological stressors, which are not always present or may not be readily identifiable.
Diagnostic criteria for FND have been proposed, but are not universally accepted, and have varying rates of interrater reliability, depending on the symptom presentation (high for non-epileptic psychogenic seizures; poor for other FND). For this reason, diagnosis remains very challenging.
Recent recommendations suggest that diagnosis should be based on positive clinical findings and supported, when necessary, by laboratory or ancillary investigation findings. Certain FND subtypes are more difficult to correctly diagnose than others. More importantly, laboratory-supported diagnosis is possible. Valid and reliable laboratory/ ancillary investigations depend on the identification and development of biomarkers. This will facilitate the research needed to advance clinical management of FNDs.
Gathering high-level evidence through clinical trials for management and treatment of FND is hampered by limitations in available outcome measures. FND pose unique challenges to developing and/or validating outcome measures, given the heterogeneity and variability of symptoms, the influence of subjective factors, and the prevalence of confounding comorbidities. This prompts the need for research focused specifically on biomarkers, clinical endpoints, and clinical outcome assessments (COAs) in FNDs. Electrophysiological, functional and structural imaging, and behavioral biomarkers have particular potential relevance to FND.
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. Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers. Categories of biomarkers include: Susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, safety.
Analytical Validation is defined as 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. 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.
Clinical Validation is defined as establishing that the biomarker acceptably identifies, measures or predicts the concept of interest. This includes defining the sensitivity, specificity, area under the receiver operating characteristic curve, positive predictive value, and negative predictive value.
The FOAs associated with this announcement allow the discovery, analytical, and clinical validation of biomarkers for FNDs. Applications aiming for clinical trial readiness or involving clinical outcome measures should be directed to the relevant FOA.
Application and Submission Information
This notice applies to due dates on or after February 5, 2022 and subsequent receipt dates through January 8, 2025.
Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Scientific/Research Contact(s)
Codrin Lungu, MD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 3014969135
Email: lunguci@ninds.nih.gov
Peer Review Contact(s)
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).
Financial/Grants Management Contact(s)
Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov