Clinical Trial Readiness for Rare Diseases, Disorders and Syndromes

Clinical Trial Readiness for Rare Diseases, Disorders and Syndromes is sponsored by National Center for Advancing Translational Sciences (NCATS) / National Institutes of Health (NIH). These grants support projects focused on collecting the data needed to move promising rare disease therapies and diagnostics to clinical trial.

PAR-25-450: Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R21 Clinical Trial Not Allowed) Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Center for Advancing Translational Sciences ( NCATS ) Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ) Funding Opportunity Title Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R21 Clinical Trial Not Allowed) R21 Exploratory/Developmental Research Grant April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025.

See Notice NOT-OD-24-084 . August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 .

August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity See Section III.

3. Additional Information on Eligibility . Assistance Listing Number(s) Funding Opportunity Purpose This Notice of Funding Opportunity (NOFO) invites researchers to submit applications for support of clinical projects that address critical needs for clinical trial readiness in rare diseases.

The initiative seeks applications that are intended to facilitate rare diseases research by enabling efficient and effective movement of candidate therapeutics or diagnostics toward clinical trials and to increase their likelihood of success.

This could be through the development and testing of rigorous biomarkers and clinical outcome assessment measures or by defining the presentation and course of a rare disease to enable the design of upcoming clinical trials. Funding Opportunity Goal(s) NCATS' mission is to turn research observations into health solutions through translational science.

We work to develop or enhance the development, testing, and implementation of diagnostics and therapeutics for a wide range of diseases and conditions.

Key approaches include understanding what’s similar across diseases to spur multiple treatments at a time, developing models that better predict a person’s reaction to treatment, enhancing clinical trials so results more accurately reflect the patient population, and leveraging real-world data and data science approaches to address public health needs.

Facilitating these approaches are our robust partnerships with other government agencies, including other NIH institutes, centers, and offices; industry; academia; nonprofit organizations; and patients, patient advocates, and other communities. NCATS' vision is to bring more treatments for all people more quickly.

Open Date (Earliest Submission Date) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II.

Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V.

Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII.

Other Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Attaining effective therapies for rare diseases is challenging due to their low prevalence resulting in fewer patients, clinicians, researchers, and resources compared to common diseases.

This leads to gaps in our understanding of a rare disease's natural history, and a dearth of suitable biomarkers or clinical outcome measures, or of other components needed to design, conduct, and interpret rigorous clinical trials. This Notice of Funding Opportunity (NOFO) invites researchers to submit applications for support of clinical projects that address critical needs for clinical trial readiness in rare diseases.

The Division of Rare Diseases Research Innovation (DRDRI) within the National Center for Advancing Translational Sciences (NCATS), along with the National Institutes of Health (NIH) Institutes and Centers (ICs) listed in Part 1, intend to facilitate rare diseases research by enabling efficient and effective movement of candidate therapeutics or diagnostics toward clinical trials and to increase their likelihood of success.

This could be through the development and testing of rigorous biomarkers and clinical outcome assessment measures or by defining the presentation and course of a rare disease to enable the design of upcoming clinical trials.

The NIH supports translational and clinical research on a broad range of diseases that are defined as rare; that is, diseases affecting fewer than 200,000 individuals in the United States (per the Rare Diseases Act of 2002). Progress in data science and an increased understanding of disease genetics lead experts to agree that more than an estimated 10,000 rare diseases are affecting millions of people in the United States.

Most are serious or life-threatening, leading to significant morbidity and mortality, and the majority affect children. Despite advances in our understanding of the causes and mechanisms of many rare diseases, effective treatments are available for approximately 5%.

To address this significant public health concern, the NIH investment into discovery research has contributed to unprecedented opportunities to translate scientific advances into better treatments. Gene therapy and related approaches are an example of opportunities that have resulted from technological advances.

However, to evaluate such potentially transformative treatments, researchers, biopharmaceutical companies, and regulators need high-quality natural history data, as well as biological and clinical outcome measures fit for the intended purpose. The absence of such information often represents a bottleneck in therapy development for many rare diseases.

This initiative aims to support studies that address these gaps in understanding of disease natural history and appropriate outcome measures, including biomarkers. Given the large number of rare diseases and the limited funding available, this initiative will focus on studies for which there are clinical development candidates for the indication(s), and for which there are unmet medical needs.

The initiative will promote partnerships among academic investigators, industry, and patient groups, and will encourage interactions with the U.S. Food and Drug Administration (FDA). Use of existing data standards, tools, information technology platforms, and candidate clinical outcomes measures and biomarkers will also be encouraged, rather than the discovery or de novo development of such tools and resources.

This NOFO describes a specialized type of clinical research that is intended to provide data necessary for the design of future clinical trials. Clinical trial readiness is the state of having validated clinical research tools and knowledge of disease natural history necessary for the design of efficient clinical trials.

Validated clinical research tools can include biomarkers or clinical outcome assessment measures that are fit-for-purpose within a defined context of use relevant to the clinical trials.

Knowledge of disease natural history necessary for clinical trial design can include characteristics for stratification or determining inclusion and exclusion criteria; the stage of disease progression that may be responsive to treatment; and data needed for determining sample size through power calculations.

This NOFO uses terminology defined in the BEST (Biomarkers, EndpointS, and Other Tools) Resource , which was developed by the FDA-NIH Biomarker Working Group. Investigators are encouraged to use the terms below, where appropriate in their applications. Guidance to reviewers will include these definitions as a way to promote consistent evaluation of the applications.

(See https://www. ncbi. nlm.

nih. gov/books/NBK338448 for reference to the BEST Resource's glossary for the following definitions.) Biomarker – 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. Clinical outcome assessment (COA) – An assessment of an outcome that reflects how an individual feels, functions or survives.

The four types of COAs are clinician-reported, observer-reported, patient-reported, and performance outcomes. Context of Use (COU) – A statement that fully and clearly describes the way the medical product development tool is to be used and the medical product development-related purpose of the use.

Concept – In a regulatory context, the concept is the aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to capture (or reflect). Validation – A process to establish that the performance of a test, tool, or instrument is acceptable for its intended purpose.

For this NOFO, the intended purpose should be the collection of data in a clinical trial that will be used to determine whether to move forward with the intervention being tested to a later stage trial or for regulatory approval. Applications to this NOFO should focus on clinical validation.

Clinical validation is defined as a process to establish that the test, tool, or instrument acceptably identifies, measures, or predicts the concept of interest. Biochemical and molecular biomarkers should have substantial data supporting analytical validation collected prior to submission of an application to this NOFO.

Analytical validation is defined as a process to establish that the performance characteristics of a test, tool, or instrument are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include specimen collection, handling and storage procedures).

This is validation of the test’s, tool’s, or instrument’s technical performance, but is not validation of the item’s usefulness. To optimize clinical trial readiness, there needs to be sufficient understanding of the rare disease to permit design, conduct, and interpretation of rigorous clinical trials. FDA published final guidance on considerations for the development of drugs and biological products for rare diseases.

This NOFO is intended to support studies that address some of the issues presented in this guidance document, including the need for adequate understanding of the course of the disease and the need for sensitive and reliable biomarkers and outcome measures to be used during a clinical trial.

Applicants are expected to have clinical expertise for the rare disease under study, including the capability for measuring COAs and analyzing appropriate biomarkers where applicable. Applicants should also have sufficient numbers of rare disease patients for inclusion in the study or have access to additional patients through collaboration.

Projects appropriate for this initiative need not be high-risk/high-reward studies; however, they should advance the field by facilitating clinical trial readiness through the development of missing components that are essential for rigorous clinical trials. Projects should be distinct from those supported through the traditional R01 mechanism.

Projects that are appropriate for this NOFO should focus on diseases that lack critical components of trial readiness and should have candidate therapeutics that will be ready for testing in upcoming clinical trials after the trial readiness study is completed.

For the purpose of this initiative, clinical trial readiness can include two categories of projects: 1) Those that utilize sensitive, reliable, valid, and responsive tools to identify or select appropriate participants for clinical trials or to measure the effects of interventions. These tools include COA measures and biomarkers.

Investigators are encouraged to use or modify existing resources, validate existing tools in specific rare disease populations, or add components to existing disease-specific tools (such as symptom scales). 2) Those that define the presentation and course of the rare disease in ways that are essential for the design of upcoming clinical trials (e.g., retrospective projects; longitudinal or cross-sectional approaches).

Leveraging Existing Research Resources Applicants should leverage existing research resources for their clinical trial readiness studies. Such resources may include existing clinical research networks such as the Rare Diseases Clinical Research Network ( RDCRN ), NeuroNEXT , or other existing networks that have successfully conducted studies of rare diseases.

Also, applicants should leverage existing research resources to streamline multi-center studies, such as the SMART IRB . Leveraging the resources and support from advocacy groups, private research foundations, academic institutions, other government agencies, and the NIH Intramural program are also encouraged.

Researchers interested in conducting trial readiness studies through RDCRN should contact the NCATS Scientific/Research Contact listed in the Agency Contacts section below early in the process of designing the study. Studies that leverage the resources of ongoing clinical trials or longitudinal studies supported through other Federal or private funds are also encouraged.

Researchers may consider collecting data to validate new or improved COA measures or biomarkers as ancillary studies to ongoing clinical trials or longitudinal studies. This NOFO will support applications for testing of biomarkers or outcome measures so that they are ready for use in multi-site studies.

Biochemical or molecular biomarkers should include justification that describes accuracy, precision, analytical sensitivity, analytical specificity including interfering substances, dynamic range, and expected normal values.

For imaging, radiological, or physiological biomarkers, the justification should provide preliminary data on the accuracy, reproducibility, sensitivity, and specificity as determined by study of a patient cohort (but not necessarily in the same rare disease).

An appropriate study could start with a small, manageable set of well-justified candidate biomarkers, and based on data acquired during this study, be narrowed down to one or a few appropriate biomarkers to better characterize or validate for use in a clinical trial.

Examples of studies intended to be supported through this NOFO include, but are not limited to, the following: Studies aimed at the clinical validation of biomarkers or COAs with defined contexts of use in specific rare disease populations. Studies to develop or incorporate patient-reported or patient-centered outcomes.

Studies to characterize rare disease patient cohorts regarding COA measures, biomarkers, genetic, epigenetic, or physiological factors that will be used to stratify patients or determine inclusion/exclusion criteria in upcoming clinical trials.

Studies to characterize rare disease patient cohorts using candidate outcome measures to establish the variability of measures as needed for accurate power calculations or to determine the appropriate duration of upcoming clinical trials. Studies evaluating the responsiveness of biomarkers or COAs through the observation of patients who are receiving treatment as part of their clinical care.

Studies to address knowledge gaps for clinical trial planning that also pilot innovative recruitment strategies for all populations who would be candidates for participation in upcoming rare disease trials. Studies that modify use of a tool in a specific rare disease population, such as the addition of disease-specific modules to an existing tool (e.g., disease-specific symptom scales).

Ancillary studies that leverage ongoing clinical studies supported through other sources of funding. Applications Not Responsive to this NOFO The following types of studies are not responsive to this NOFO. Applications proposing such studies will be considered non-responsive and will not be reviewed or considered for funding.

Studies which do not clearly address a rare disease, defined as diseases affecting fewer than 200,000 individuals in the U.S. Evidence supporting rare disease classification may include references confirming the prevalence and additional information if the disease has been granted orphan status by the FDA.

Rationale should also be provided if focusing on a rare variant or subset of a more common condition, along with the scientific basis for separately studying the rare variant or subset. Natural history studies aimed at broadly exploring disease pathophysiology, genetic or epigenetic mechanisms with no direct connection to an upcoming clinical trial.

Studies of patient genetics or pathophysiology will be responsive only if characterization is necessary for stratifying trial participants or determining inclusion/exclusion criteria in upcoming clinical trials. Studies of biomarker discovery or assay characterization. Applications that propose only to maintain patient registries.

NCATS and the NIH ICs listed in Part 1 will not provide support to maintain or acquire additional data on study participants beyond the end of the clinical trial readiness grant. Applications that request support for infrastructure to establish new clinical trial networks. Applicants should leverage existing resources such as existing rare disease-focused networks (for example, the RDCRN .

Studies aimed at determining the safety, pharmacokinetics, efficacy, or effectiveness of an intervention (drug, biologic, device, etc.) in humans. Applications assigned to participating ICs that address the mission and priorities of ICs not participating in this NOFO will not be prioritized for funding. See Section VIII.

Other Information for award authorities and regulations. Section II. Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO. Not Allowed: Only accepting applications that do not propose clinical trials.

Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Applications can request budgets that are up to $275,000 direct costs for the 2-year project period of the award.

No more than $200,000 direct costs may be requested in any single year. The scope of the proposed project should determine the project period. The maximum project period is 2 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions - Includes all types Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are not allowed. Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award.

All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually . The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registrations; all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov – Applicants must have an active SAM registration in order to complete the Grants.

gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.

If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application. A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for review. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: Evidence Supporting Rare Disease Classification – The Research Strategy should include a paragraph with the heading, " Evidence Supporting Rare Disease Classification ".

If the application does not include the following information, then it will be considered non-responsive and will not be reviewed.

This section should provide the evidence that the disease/condition being studied is classified as a rare disease; i.e., there are 200,000 or fewer patients in the U.S. This section may include one or more references confirming the prevalence of the disease/condition that is the primary focus of the research application. If the disease/condition has been granted orphan status by the FDA, provide this information in this paragraph.

If it is a rare variant or subset of a more common condition, provide the rationale for focusing a trial readiness study on this variant or subset. Describe the scientific basis for separating biomarker/clinical outcome assessment (COA) validation for this rare variant or subset from that of the common condition.

Need for Clinical Trial Readiness – The Research Strategy should include a subsection with the heading, " Urgent Need for Clinical Trial Readiness ". This subsection should describe the need for conducting the trial readiness study at this time, or how the project addresses a critical barrier or bottleneck to progress toward clinical trials.

Applicants should describe the clinical trial design issues (e.g., biomarker or COA validation, data for power calculations, defining inclusion/exclusion criteria, determining the duration of the trial, etc.) that will be addressed by this trial readiness study. Describe the potential impact of the proposed studies in addressing significant needs in the design and increasing the likelihood of success of upcoming clinical trials.

This section should also contain the following: A brief description of the state of development of candidate therapeutics or devices for this rare disease (even if the current applicants are not involved in the development of those therapeutics/devices). Timelines for the advance of therapeutics/devices to clinical trials. A brief description of the clinical trial(s) that would be enabled by the results of this trial readiness study.

Provide letters of support (below) from the researchers who expect to conduct upcoming trials. Outline the next steps for moving into a clinical trial if the proposed study is successful—that is, provide the rationale that a clinical trial is feasible in the near future. Include a brief description of the currently available COA measures and/or biomarkers.

If appropriate for the proposed study, describe how the study will result in advancements over the currently available measures/biomarkers. If the current measures/biomarkers are considered inadequate or insufficiently developed for use in upcoming trials, describe their limitations and how those limitations may compromise the success of upcoming trials.

If the proposed trial readiness study is ancillary to an ongoing clinical trial or longitudinal study, describe that study and provide a letter of support (below) from the study's lead PD(s)/PI(s). Explain how the trial readiness study will lead to improvements in the design of future trials above that of the ongoing study.

Describe any gaps in knowledge regarding the disease natural history that need to be addressed to achieve clinical trial readiness. Explain how the lack of this knowledge will compromise clinical trial design and how this study will overcome current obstacle(s).

Briefly describe the role of companies or voluntary health organizations that are currently engaged or potentially available for clinical trial readiness studies or clinical trials for this disease, if applicable. Biomarkers and Their Context of Use If biomarker validation is proposed, the application should contain a subsection with the heading, " Biomarkers and Their Context of Use ".

This section should describe each biomarker that will be tested for validation and the context of use (COU). The COU should explain how, when, and why the biomarker is to be used in a clinical trial. Biochemical/molecular biomarkers should have analytical validation before applying for a clinical trial readiness award through this program.

Applications should include a table listing each biochemical/molecular biomarker to be tested for clinical validation, the intended use (e.g., diagnostic, predictive, treatment response, pharmacodynamic), the method of the assay (e.g., mass spectrometry, ELISA, surface plasmon resonance), the sensitivity, dynamic range, and expected normal values.

Other characteristics of the assay such as accuracy, precision, specificity including interfering substances, etc. should also be described in the text of this subsection. Describe what a graph of each biomarker measurement over time is expected to show (e.g., linearly decreasing measurement, sigmoidal curve, etc.) and the expected relationship of the biomarker to COA measures (e.g., inversely proportional).

For imaging, radiological, or physiological biomarkers, the rationale should provide preliminary data on the accuracy, reproducibility, sensitivity, and specificity as determined by study of a patient cohort (but not necessarily in the same disease). Describe the equipment (i.e., instrument manufacturer and model) and expertise available at each clinical site for measuring the biomarker(s).

Plans for the training of personnel at each site in the use of the standardized protocols, data quality control strategies, reference standards and approaches for verifying instrument calibration at the clinical sites should also be described as appropriate. Clinical Outcome Assessment Measures Clinical outcome assessment (COA) measures can be clinician-, observer-, or patient-reported, or performance outcomes.

If COA measure validation is proposed, applications should provide a list of each COA measure that the study aims to clinically validate. Describe the construct validity (i.e., hypothesized relationship with other disease characteristics) and content validity (i.e., extent to which the COA measures the concept of interest) for each COA measure. Describe plans for analysis of test-retest and inter-rater reliability.

Describe Rasch analysis for COA measure optimization if appropriate. Natural History of Disease Studies on the course of the disease may only be proposed for the purpose of developing readiness for upcoming clinical trials. If studies on aspects of the natural history of the disease are being proposed, describe any existing observational studies that may address