National Heart, Lung, and Blood Institute (NHLBI)
August 23, 2019- Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-137
The purpose of this Funding Opportunity Announcement (FOA) is to support multiple Protocol Leadership Groups (PLGs) that will conduct phase II trials within the NHLBI Pulmonary Trials Cooperative (PTC) clinical trials network. The PTC will include multiple Protocol Leadership Groups (PLGs) and a single Network Management Core (NEMO) and will conduct multiple simultaneous phase II clinical trials that test innovative disease modifying therapies (DMT) for chronic lung diseases.
A companion FOA (RFA-HL-21-012) seeks applications for the Network Management Core (NEMO).
May 01, 2020
30 days prior to the application due date
07/24/2020, 06/01/2021, 06/01/2022
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
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.
December 2020, October 2022, January 2023
January 2021, January 2022, January 2023
Conformance to all requirements (both in the Application Guide and the FOA) 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.
Most chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma currently have no cure, and available treatments are aimed primarily at symptom abatement. COPD affects at least 15 million people in the U.S., with >150,000 deaths yearly (and >60% of deaths are among those over 75 years of age). Although IPF is considered a rare lung disease (affecting 200,000 people or fewer), it causes about 40,000 deaths annually, with a median survival of only 3 years after diagnosis. Asthma affects >24 million people in the U.S., and >7% of these patients have a severe form of the disease. Other chronic lung diseases, including pulmonary sarcoidosis and lymphangioleiomyomatosis (LAM), are characterized by irreversible subversion of the lung architecture with progressive loss of functional lung tissue. Hence, there is an urgent need to develop innovative therapeutic approaches that, by interfering with underlying pathophysiological mechanisms, will significantly delay or permanently change the clinical progression of a chronic lung disease. Such a treatment may be considered a disease-modifying therapy (DMT).
This funding opportunity announcement (FOA) seeks applications for Protocol Leadership Groups (PLGs) which will conduct phase II trials to test innovative disease modifying therapies (DMT) for chronic lung diseases. These trials will be designed to demonstrate a lasting effect on disease course, clinical outcomes or biomarkers that are known indicators of a key, underlying pathophysiological process of the chronic disease. No single type of evidence is invariably required to substantiate the efficacy of DMTs, but potential outcomes that could support the efficacy of a DMT may include an increase in drug-placebo difference over time for a measure of disease severity or a delay in disease-specific milestones of progression. Therapies aimed at symptom relief do not qualify as DMTs under this RFA; applications that propose to utilize therapies aimed at symptom relief will not be reviewed.
Each successful application will serve as a Protocol Leadership Group (PLG) for the NHLBI Pulmonary Trials Cooperative (PTC) clinical research network. Each PLG will design and oversee conduct of a specific clinical trial within the PTC, which will include multiple PLGs and a Network Management Core (NEMO). The PTC is designed to simultaneously conduct multiple clinical trials in chronic pulmonary diseases, including but not limited to chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), asthma, adult cystic fibrosis (CF), adult primary ciliary dyskinesia (PCD), pulmonary hypertension (PH), and sarcoidosis, but excluding acute respiratory distress syndrome and pediatric lung diseases. Further details of the responsibilities and interactions of the PLGs and the NEMO are provided below.
This FOA will utilize a bi-phasic, milestone-driven mechanism of award. Finalization of the trial protocol, regulatory approvals, and other steps necessary to prepare for enrollment will occur with support from an R61 grant during the first phase. Based on satisfactory progress, continued scientific importance of the question being addressed, and availability of funds, NHLBI may elect to award the subsequent R33 grant to support PLG activities during the trial period itself. PLG applicants are encouraged to propose multiple PD/PIs as needed to provide adequate expertise in biostatistics, clinical trial design, and study coordination.
By studying multiple chronic pulmonary conditions in a single large program, the PTC will enable studies across a wide range of chronic pulmonary diseases; encourage studies of specific subsets of patients; involve a wide range of institutions in the recruitment, retention and follow-up of research subjects; and increase the efficiency of subject recruitment at individual sites by strongly encouraging the use of electronic medical information systems for the identification of potential research subjects. A companion FOA (RFA-HL-21-012) requests applications for a limited competition for the Network Management Core (NEMO).
It is important to recognize that the scope of this FOA differs from the previous PTC program (see: RFA-HL-15-015)by focusing exclusively on investigations of disease-modifying therapies (DMT). A DMT is here defined as an intervention(s) that results in a significant delay or permanent change in the clinical progression of a chronic lung disease by interfering with the underlying pathophysiological mechanisms of the disease. DMT efficacy may be demonstrated through an appropriately designed clinical trial using either clinical outcomes, biomarkers or a combination of these. In this context, biomarkers are defined as objective measures that reflect key pathobiological processes of the disease and are also useful for quantifying pharmacological responses to a therapeutic intervention. DMT efficacy may also be indicated, in some situations, by a reduction in the dosage of medication(s) required to manage the disease.
Each awarded PLG will be expected to finalize the design of a single, phase II clinical trial; to provide a Lead Investigator(s) for oversight of the study during implementation; and to perform all aspects of centralized protocol data management, including support for screening and randomization, electronic transfer and collection of individual data in a central database, error checking and data quality control, and study analysis. In addition to the Lead Investigator (typically a pulmonologist), PLG teams are strongly encouraged to include an investigator with expertise in clinical trial statistical design and analysis as required to produce a complete protocol and manage the data collected. To this end, multiple PD/PI applications are encouraged. The PLGs are expected to cooperate with the PTC Network Management Core (NEMO, see companion FOA RFA-HL-21-012) and a network of 20-40 Clinical Centers assembled by the NEMO. The NEMO will coordinate Clinical Center activities and disburse protocol funds to support trial operations. The trials must focus on adult chronic pulmonary diseases and be feasible within the constraints of time, budget, and subject availability imposed by the requirements of these FOAs. The exact number of trials funded will depend on the nature and extent of the investigations proposed as well as on the availability of funds. Understanding fiscal and organizational constraints, NHLBI strongly encourages the establishment of public-private partnerships to assist with patient identification and/or drug procurement.
This FOA will utilize a bi-phasic (R61/R33), milestone-driven mechanism consisting of a start-up phase of up to one year (R61), and a full enrollment and clinical trial execution phase of up to four years (R33). PLGs will have primary responsibility for developing study forms and implementing a data management system for the specific protocol they propose. PLGs are also tasked, in concert and coordination with each other and the NEMO, with establishing a data-harmonization committee aimed at developing common measures that can be used by researchers across the PLG studies. By using these common measures, researchers in and outside the PTC will be able to more easily compare and combine datasets to detect more subtle and complex associations among variables, thereby promoting greater collaboration, efficiency, and return on investment.
PLGs will also process, tabulate and report, in accordance with NHLBI policies, adverse events (AEs), provide quality control for the trial they propose, analyze study data, and draft the main study manuscript. If biospecimen collection is proposed as part of the trial, this should be appropriately justified in the PLG application, and responsibility for maintaining a biospecimen repository will reside with the PLG. The PI(s) of each PLG will serve on an operations committee (OC) with primary responsibility for implementation, oversight, continuing evaluation, and reporting of PTC studies. The OC will also include the PI(s) of NEMO, rotating representatives of the Clinical Centers, one program official from the NHLBI, and a Chair appointed by the NHLBI. The PI(s) of each PLG will vote only on general issues and on matters regarding their own protocol. A Data and Safety Monitoring Board (DSMB) will also be established in accordance with NHLBI policies (see http://www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm) to act as an independent advisory group to the NHLBI Director on issues of human subject safety and privacy, study integrity, and study progress.
A key characteristic of this FOA is the use of core milestones. A core milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones, which will be established for both the R61 and R33 phases of the project, must be performance-based and serve to assure completion of the trial on time and on budget. PTC trials are expected to be conducted with a high degree of efficiency and with streamlined administrative procedures wherever possible, so applicants should employ project management principles as appropriate. Applicants are also strongly encouraged to develop contingency plans to proactively confront potential delays or disturbances in meeting the milestones.
If required by the nature of the investigation, each PLG will create and operate a biospecimen repository necessary for a protocol, assuring linkage of biospecimens to clinical data in a manner that protects human subject privacy; and store and retrieve specimens under appropriate conditions and with provision for catastrophic events such as power failure. Each PLG will be expected to coordinate with the NHLBI BioLINCC program to ensure that study procedures are compatible with that program's requirements for bio-specimen collection, labeling, and storage and will allow eventual transfer of residual biospecimens to that repository.
Complementary Roles of PLGs and NEMO
Each PLG will have complementary roles to the NEMO in the management and conduct of its own phase II trial. NEMO will recruit and manage a network of clinical sites to implement protocols of the PLGs. The following table summarizes and clarifies the complementary functions. For a more detailed description of the NEMO, see the companion FOA RFA-HL-21-012.
Table: Summary of Functions
Protocol Leadership Groups (PLGs)
Network Management Core (NEMO)
Develop a protocol, serve as Lead Investigator for that protocol, and manage and analyze study data
Obtain Food and Drug Administration (FDA, (http://www.fda.gov) regulatory approval for the trial, including Investigational New Drug/ Investigational Device Exemption (IND/IDE) or exemption as needed
Develop and maintain a secure web-based data entry system and associated case report forms. To the extent possible common data elements and reusable forms that are applicable in trials of different interventions and in a variety of pulmonary diseases should be employed. Make forms available to NEMO for use in other trials.
Randomize subjects to different study arms
Register the trial and maintain updated status reports of the trial on ClinicalTrials.gov (https://clinicaltrials.gov )
Procure drugs and placebos, test and label, as needed Manage protocol data; provide data quality assessment and quality control; perform data cleaning and statistical analyses of data; use a data system that protects patient confidentiality at all steps in the submission and analysis of clinical trials data and ensure the technical integrity and security of the dataset
Store and analyze biospecimens (if part of the protocol)
Prepare manuscripts and publish results
Prepare datasets for submission to an NHLBI data repository
Process, tabulate and report AEs in accordance with NHLBI policies
Identify study outcomes or unanticipated problems that might compromise subject
safety and necessitate changes or termination of the studies
Generate and submit to NEMO periodic reports, in an agreed upon format among all the PLGs and the NEMO, for the NHLBI and the DSMB that NEMO will forward to those entities
Organize a network of Clinical Centers capable of conducting the breadth of PTC trials. With approval from NHLBI, distribute funds to activate efficient processes for identifying and contacting potential research participants
Train and certify Clinical Centers staff
Verify IRB approvals
Create and maintain a 508 compliant website
Maintain official study documents, inclusive of manuals of Standard Operating Procedures (SOPs)
Schedule, organize, and accommodate all PTC committees and board meetings and teleconferences
Manage and distribute protocol-specific funds to the Clinical Centers on a per-patient basis via master trial agreements
Monitor clinical center activities with site visits as needed
Generate NEMO specific periodic reports for distribution to the NHLBI and the DSMB
Distribute to the NHLBI and the DSMB the PLGs’ reports in an agreed upon format among all the PLGs and the NEMO,
Monitor participant retention, protocol adherence, research subject safety and protection according to NHLBI and other government and regulatory policies Report the demographic characteristics of enrolled populations and implement remediation plans imposed by NHLBI to ensure nationally representative participation of women and minorities in PTC studies
Identify study outcomes or unanticipated problems that might compromise subject safety and necessitate changes or termination of the studies
Phases of Award
The R61 phase will support finalization of the protocol and the informed consent/assent document; the development of the manual of operations and procedures, case report forms and other resources necessary for performance of the protocol; further development of study partnerships; and review of the protocol by the NHLBI-established Data and Safety Monitoring Board; and Institutional Review Board approvals of the trial.
For trials using an FDA regulated product and requiring an IND or IDE application to administer the product to humans, investigators must (1) secure IND authorization or IDE approval and (2) provide documentation of this authorization or approval to NHLBI before a funding decision for the R61 phase will be made. Necessary drugs, devices, or other resources must be obtained by the end of the R61 award to allow for the successful launch and execution of the proposed clinical trial in the R33 phase.
Investigators and NHLBI will review and mutually agree upon final revised milestones that will be included in the Terms and Conditions of the grant, if awarded. Transition from the R61 to the R33 phase is contingent on the successful completion of all mutually agreed upon milestones for the R61 phase of the study. The overall planned enrollment will be agreed upon between the grantee organization (or recipient) and the NHLBI prior to an award.
Enrollment of participants into the clinical trial is expected to begin before the end of the R61 phase to demonstrate readiness and promote completion of the trial on time and within budget. NHLBI will conduct an administrative review approximately 11 months into the R61 phase to determine progress toward achievement of milestones included in the Notice of Award. Milestones and timelines for the R33 phase may be revised and finalized at the time of the R61/R33 transition. Less than satisfactory progress in the R61 phase may lead to phasing out the award. Milestones must address timing of overall recruitment/enrollment and retention goals, including accrual goals for women, minorities, and individuals of all ages including children and older adults. It is expected that performance of core milestones, such as planned enrollment goals, will be shared on a regular basis through eConnect, an NHLBI platform that will facilitate transfer of electronic information to NHLBI.
Subject to NHLBI funding availability and scientific priorities, R33 awards will be made after administrative review with specific attention to the extent to which all agreed-upon milestones have been met. If the R33 is funded, NHLBI will review the progress of the clinical trial on a regular basis. Slower than anticipated progress towards meeting milestones will result in a re-evaluation of the award by NHLBI including whether the objectives of the trial can be met on time and within budget. If milestones have not been satisfactorily met, subsequent funding years may not be approved and phasing out of the award may be required.
NHLBI policies regarding milestones and relevant clinical research/studies policies are described in the following: NHLBI Accrual of Human Subjects (Milestones) Policy.
This FOA encourages investigators experienced in the conduct of clinical trials to apply. Early Stage Investigators with appropriate experience are encouraged to apply provided they will receive appropriate scientific support from senior investigators.
Clinical Trials Not Supported by this FOA
The following types of clinical trials are not intended to be supported by this FOA:
Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
NHLBI intends to commit total costs up to $630,000 in FY2021, $315,000 in FY2022, and $630,000 in FY2023 to fund up to two new awards in FY2021, one in FY2022, and two in FY2023. The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Application budgets may not exceed direct costs of $200,000 per year. Actual budget amounts will depend on annual appropriations.
Investigators are encouraged to request what is well-justified for their research program.
The maximum project period of the combined R61 and R33 phases is 5 years, with up to 1 year for the R61 phase and up to 4 years for the R33 phase. The scope of the proposed project should determine the requested project award period.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) 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. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
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.
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 SF424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
Facilities and Other Resources:
Describe how the infrastructure at the PLG will facilitate the efficient operation of the proposed clinical trial, including project management tools that will be used to coordinate the conduct of the trial with the NEMO.
Other Attachments: The attachment listed below must be provided or the application will not be peer reviewed.
1) Trial Management Plan: A description of how the proposed trial will be managed must be provided as an attachment using the filename "Trial Management.pdf" and may not exceed 5 pages. Describe the strategy that will be used throughout the project to ensure that management activities of the clinical trial are met, including directly supporting the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives. The trial management plan should demonstrate the applicant’s ability to achieve the goals of the clinical trial within budget and on time and to successfully manage and mitigate risks. This description should include:
Key methodology and standard operating procedures governing resource management, study deployment, operations/execution, and study closure
Procedures for orderly project closure
The experience of each PD/PI and all Key Personnel must be carefully documented, and roles and responsibilities must be well defined. In addition, the respective responsibilities and authority of each PD/PI must be specified. Include biosketches for a multidisciplinary team of appropriate personnel (clinician, statistician, data manager, study coordinator(s), etc.) to facilitate the implementation of all aspects of the clinical trial, including recruitment of subjects, design/implementation of the trial protocol, and coordination of roles/responsibilities.
All Key Personnel who are major contributors to the study must provide an NIH Biosketch whether or not they are budgeted. Describe the experience of key scientific personnel in the conduct of clinical trial coordination and management, including the following:
All instructions in the SF424 (R&R) Application Guide must be followed.
Provide modular, annual budgets that will enable the trial to meet its milestones. Provide estimates of the total direct costs of implementing the protocol on a per-patient basis (e.g., clinical costs that are not part of usual care such as tests, sample and data collection, supplies, drugs) as part of the budget justification. Include costs of estimated hours for enrollment (screening and consent) for PD/PI and coordinator, and estimated hours for protocol implementation (execution).
The protocol costs (per year and total) should reflect costs for a phase II trial that aims to recruit up to about 400 participants. The protocol costs will be funded through the NEMO companion FOA (see: RFA-HL-21-012, Section IV.2. R&R Budget) and will be managed by and distributed to the recruiting centers by the NEMO. While the protocol costs of the trial must be defined and justified in the PLG application, they should not be included in the modular budget of the PLG.
If partial support is to be provided by sources other than NHLBI, the value of these contributions should be presented in detail in the budget justification and in a separate budget table identified as non-Federal cost share. Third Party support of the proposed research activity (if approved) will be incorporated as a Term and Condition of Award. If the Third-Party support ceases and the trial is no longer tenable without the Third-Party support, a close-out plan may be requested by NHLBI.
Annual budget requests should include funding only for PLG activities that will be performed in that year and only for the costs that will be required for the activities to be performed in a given year. Generally, the NHLBI expects the requested costs in year 1 to be lower than in the following years, depending on recruitment targets. Include budget support, if needed, for up to two PLG personnel to attend one steering committee/executive committee meeting per year in the Bethesda, MD, area. If applicable, budgets should include all costs associated with Data Safety and Monitoring Board (DSMB) activities, including preparing reports for the DSMB and travel to at least one DSMB meeting per year.
Specific Aims: Briefly describe the overall scientific rationale for the clinical trial.
Research Strategy: The Research Strategy should present an overview of the state of the science and relevance of the trial, a detailed discussion of the specific protocol, and the approach to data collection, analysis, and dissemination. In the overview, address the study research objectives and the overall conduct of the clinical trial: include how the proposed treatment qualifies as DMT; what will the treatment target in disease pathobiology and what measures will be used to assess this (i.e., a biomarker/measures which will show the treatment is DMT). The following should be addressed:
Significance: The significance of the proposed clinical trial and importance of the question must be clearly stated. It is particularly important to provide a discussion of the evidence supporting equipoise. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance science. Include a description of how results will impact health or clinical care. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance.
Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms.
Approach: As detailed below, the research Approach section should include detailed descriptions of the supporting data and the experimental strategy, including study design, power estimates, and proposed statistical analyses. This section should include the following named subsections.
Supporting Data: Describe the formative clinical studies (including any pilot/feasibility studies) that provide the basis for the proposed clinical trial. Include other research as appropriate to demonstrate that the chosen approach is justified. If appropriate, include relevant data used to demonstrate that the proposed trial includes adequate numbers of subgroups of participants to allow for separate and adequately powered analyses. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial.
Experimental Approach: Describe critical features of the clinical trial that are not already included as part of the PHS Human Subjects and Clinical Trials Information form. At a minimum, this subsection should contain:
Propose and justify milestones that will be subject to peer-review. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, measurable, results-focused and time-bound. Milestones must address timing of overall recruitment/enrollment and retention goals. The milestones must address with specificity the accrual goals for women, minorities, and individuals of all ages including children and older adults. Describe the milestones that will be met in the R33 phase to address the specific aims and ensure the successful completion of the clinical trial and dissemination of its results. Core milestones of particular interest include but are not limited to:
Core R61 Trial Milestones
Core R33 Trial Milestones
Letters of Support: Letters of support from clinicians or clinical department chairs whose support is necessary for the successful conduct of the trial should be provided. If partial funding is to be provided by sources other than NHLBI, provide Letter(s) of Support signed by an authorized organization representative (AOR).
The following modifications also apply:
If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions.
Section 2 - Study Population Characteristics
2.4 Inclusion of Women, Minorities, and Children
Information on the expected Inclusion of Women Minorities and Children in the specific PLG study must be provided.
2.5 Recruitment and Retention Plan
The Recruitment and Retention Plan should address: 1) the expertise of the individual(s) responsible for screening, approaching and consenting potential participants; 2) engagement of patient advocacy groups, if any; 3) the process for identification and screening of study participants; 4) primary and back-up recruitment strategies (e.g., use of electronic health records); 5) participant retention and adherence strategies; 6) possible competition from other trials for study participants; 7) engagement of the clinical community(ies) that will play a critical role in the recruitment and retention; 8) recruitment of groups for cluster-randomized trials, if applicable.
2.7 Study Timeline
Include a table or graph of the overall study timeline. This may be a visual representation (such as a Gantt Chart) of core milestones and key project management activities. A narrative is not expected in this section.
The study timeline should include core milestones that will be reached throughout the lifecycle of the clinical trial (including both the R61 and R33 phases) and that measure progress toward successful completion of the study. Include subtasks that will be used to reach the milestones. The period of time for the study duration should be displayed in months and must include, but is not limited to, the following:
(a) when the study opens to enrollment
(b) when core milestones are met
(c) when subtasks needed to reach the core milestones are achieved
(d) when the primary analysis of study data will begin and will be completed
(e) when the submission of the primary study manuscript for publication is expected
Section 3 - Protection and Monitoring Plans
3.3 Data and Safety Monitoring Plan
Describe the process that will be utilized to identify unanticipated problems. Describe stopping guidelines and procedures for discontinuing the intervention.
3.5 Overall Structure of the Study Team
Include a description of the following:
Section 4 - Protocol Synopsis
4.1 Study Design
4.1.a Narrative Study Description
Include protocol title. Describe the protocol to be followed in each arm of the trial. Include a brief description of how the investigators will
4.1.c Interventions - Description
Describe the strategy for establishing that the intervention is disease-modifying, including critical aspects of trial design, clinical outcomes, and biomarker measurements. Provide specific information regarding dose, period of administration, choice of formulation, device specifications, if applicable, and key characteristics of related procedures such as diagnostic laboratory tests and biomarker assays.
Highlight whether the trial design will demonstrate a lasting effect of the intervention on disease course. Detail how clinical outcomes and biomarkers may show a continuing effect on the underlying pathophysiological processes of the chronic lung disease.
4.3 Statistical Design and Power
Provide a justification for the proposed sample size based on clearly defined assumptions. Explain how the outcome(s) will address the hypothesis(es) being tested. Describe plans for interim and final analyses; methods of bias control; and methods for handling missing data (as applicable). The description should be detailed enough to allow replication of the analysis by an independent statistician. If applicable, include plans for evaluation of the primary outcome(s) by race/ethnicity, sex and gender, and include relevant data to assess whether or not the trial includes adequate numbers for valid analyses of subgroups. In addition, justify adequacy of power to analyze subgroups of participants. Adaptive designs should include a pre-specified adaptation plan that allows for clear go/no-go decisions and pre-specified analysis boundaries. Include a description of the approach to data management and validation, including data management systems, methods of data entry and cleaning, event tracking and logistics, case report forms, and methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; data confidentiality and subject privacy; plans for data and IT security; disaster recovery plans; adjudication of events (as needed); and data reports.
Section 5 Other Clinical Trial-Related Attachments
5.1 Other Clinical Trial-related Attachments
1) Clinical Trial Research Experience: Clinical Trial Research Experience information must be provided or the application will not be peer reviewed. Applicants must provide a detailed table listing the characteristics of trials that demonstrate experience in trial leadership/coordination in the last 5 years.
The table must be provided as an attachment called "Clinical Trial Research Experience.pdf" and may not exceed 3 pages.
The table columns should include:
Column A: clinical study title
Column B: investigators’ roles in the study
Column C: a brief description of the study design
Column D: planned enrollment
Column E: actual enrollment
Column F: number of sites required for enrollment
Column G: whether each study was completed on schedule or not
Column H: publication reference(s)
2) Biospecimen Justification and Management Plan: If applicable, a Biospecimen Justification and Management Plan should be provided as an attachment using the filename "Biospecimen Management.pdf" and may not exceed 5 pages.
If biospecimen collection is proposed as part of the trial, provide a justification for collection and describe plans for the development and operation of a biospecimen repository. Describe conditions for storage and retrieval of specimens with provision for catastrophic events such as power failure. Include plans for coordination with the NHLBI BioLINCC program to ensure that study procedures are compatible with the BioLINCC requirements for biospecimen collection, labeling, and storage and which will allow eventual transfer of residual biospecimens to that repository
Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
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Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.
A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?
Specific to this FOA
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?
Specific to this FOA
How strong is the project management expertise represented among the key personnel?
How well will the described roles/responsibilities of the Project Manager and other key personnel serve to ensure successful completion of the study?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?
Does the application adequately address the following, if applicable:
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified? Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity? Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?
Data Management and Statistical Analysis
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
Specific to this FOA
What strengths and weaknesses are there in the study design?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?
Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?
If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?
If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?
Specific to this FOA
Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate? Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?
Specific to this FOA
For research that involves human subjects but does not involve one of thecategories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Heart, Lung, and Blood Institute, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA. For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file. Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials by law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/.
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or supported human biomedical and behavioral interventions studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&$) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
For trials using an FDA regulated product and requiring an IND or IDE application to administer the product to humans, investigators must (1) secure IND authorization or IDE approval and (2) provide documentation of this authorization or approval to NHLBI before the award will be made. If the protocol is exempt from an IND or IDE, applicants are required to provide a copy of the exemption letter from the FDA. If the protocol is conducted under a non-US regulatory agency, equivalent documentation must be provided to NHLBI before the award will be made.If progress is deemed satisfactory in the first phase, milestones and timelines for the second phase (execution of the trial) may stay the same as originally agreed upon. In certain cases, the milestones and timelines may need to be revised and finalized prior to transitioning into the second phase of the award. If revision of the milestones is needed, investigators and NHLBI staff will review and mutually agree upon a revised set of milestones for the second phase of the trial.
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.
HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.
Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreementsare required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM)about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings.Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.
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