Key Dates

Related Announcements

PA-20-163 - Competing Revisions to Existing NIH Grants and Cooperative Agreements (Clinical Trial Optional)

Issued by

National Heart, Lung, and Blood Institute (NHLBI)

Purpose

Purpose

This NOSI aims to incorporate an implementation research question into Phase II and III NHLBI clinical trials that are part of phased awards (R61/R33 and UG3/UH3). The purpose of this NOSI is to strengthen the impact of findings from the parent study and prepare for ready uptake of the clinical study results into practice and real-world applications. The parent activity code of the existing award must be an NHLBI-funded R61/R33 or UG3/UH3 phased award.

Background

NHLBI’s Strategic Goal to Advance Translational Research seeks to advance the translation of bridging basic to clinical, clinical to practice, and population to health impact. Implementation science uses research findings to promote the uptake of clinical research into healthcare practice and health policy. Historically, implementation research occurred after clinical trials to advance the acceptance and sustainability of evidence-based practice and guidelines to populations. Implementation research may require new methods, additional funding, repeated contact of participants, an extension of data and data agreements, and other strategies to address the challenges that delay the impact of the study findings. Early in the study, the integration of implementation science is an optimal approach to improving and hasten the translation of evidence-based interventions to the intended population. Ongoing clinical trials can benefit from implementation research through the engagement of implementation science consultants, integrating data elements, including needs assessments, leading focus groups, conducting subgroup analyses, and designing sub-studies. Novel methodologies using primary and secondary data can inform subsequent implementation processes. For example, focus groups and interviewing patients, providers, and organizational leaders provide information on implementation challenges and strategies. Predictive analytics using big data (e.g., patient records, administrative data, county health reports, state-level data, etc.) inform the scale-up and sustainability of interventions from the individual to the population level. Cost analyses can determine effectiveness, benefit, and value ratios that drive healthcare care financing and policy decisions.

Innovative approaches to maximize clinical findings for timely implementation may include the use of validated effectiveness-implementation hybrid designs. State of the art, hybrid implementation designs integrate implementation data and innovation concurrently during a clinical trial to enhance effectiveness and successful implementation. There are three types of hybrid effectiveness-implementation designs: Type I) testing the effects of a clinical intervention on relevant outcomes while observing and gathering information on implementation; Type II) dual testing of clinical and implementation interventions/strategies; and Type III) testing of an implementation strategy while observing and gathering information on the clinical intervention impact on relevant outcomes.

Research Objectives

The objective of this research is to increase the use and uptake of clinical trial results by incorporating tests of implementation strategies into existing NHLBI Phased II and III clinical trials. This NOSI will support applications that propose a multidisciplinary research approach in the second phase (i.e., the R33 or UH3 phase) of the bi-phasic award. Revision supplement funds will support implementation research during the full enrollment and clinical trial execution phase (R33 or UH3 phase), not to exceed the project period of the parent award.

Applicants are encouraged to form collaborations between implementation scientists and scientists with expertise in varying disciplines (e.g., behavioral economics, informatics, data science, health systems science, shared-decision making, economics, etc.). Investigators should have a strong track record of funding in related areas, such as adherence, behavioral economics, predictive analytics, health behavior, public health, health policy, decision making, health services, comparative-effectiveness, and data analytics.

By maximizing the impact of NHLBI clinical research implementation during the clinical trial execution phase (R33 or UH3), translational research will be advanced during the intervention process, rather than after an intervention is complete.

This NOSI aims to strengthen the potential for achieving impactful implementation of NHLBI clinical research studies as they transition to the R33 or UH3 phase of award. Early integration of implementation research design into clinical trials hastens and improves the subsequent implementation process. Studies may include primary or secondary data at one or more levels of analyses (i.e., patient, provider, community, organization, state, etc.). Research designs must include proven methodologies and established implementation frameworks. Qualitative and quantitative data from needs assessments, focus groups, cost data, interviews, health surveys, electronic health records, GIS, etc. are illustrative inputs. Clinical trials may choose to blend design components of clinical effectiveness and implementation research as hybrid effectiveness-implementation design studies and are of high interest.

Potential Research Areas

Research examples that would be responsive to this NOSI include but are not limited to:

• Use of the proposed primary and secondary outcomes of a currently funded clinical trial to develop and test a mixed-methods approach to identify the primary barriers and facilitators to adherence from a patient and community perspective.
• Use of a validated instrument or questionnaire in a focus group setting involving patients, family members, practitioners, and other stakeholders, to determine the primary drivers of acceptability and sustained adherence to interventions.
• Use of available resources for integration of pertinent data from electronic health records, wireless data, GIS, etc., and innovative analytical modeling, e.g., predictive analytics, advancements in the examination of implementation barriers and facilitators in medical settings, in communities, in the home, and among individuals and the families.
• Collect and analyze cost, cost-effectiveness, and cost-benefit data of the intervention, uptake of the intervention, and implementation sustainability that inform decision making and policy decisions
• Identification of the factors to replicate and sustain the intervention with fidelity in various contexts, including low-resource settings.
• Improve the strategies in pharmaceutical and behavioral trials to optimize the impact of clinical trials for diverse populations and improve health equity.
• Develop and implement strategies to address social needs and stressors. These may include the lack of access to quality food or housing and transportation needs and partnerships with community resource organizations and other entities with the expertise to address social determinants of risk that impact intervention participation, adherence, and outcomes of clinical trials.
• Promote the adoption and maintenance of individual-level behaviors shown to improve intervention outcomes, including, but not limited to, dietary intake, physical activity, sedentary behavior, risk factor management, mental health management, and medication, and treatment adherence using innovative approaches.
• Develop and implement strategies to overcome health care system barriers and thereby improve access to care, effectiveness of patient and provider interactions, patient health literacy, education, and treatment adherence, and strengthen overall implementation of care.
• Use of rigorous mixed-method approaches to understand the facilitators and barriers to research participant engagement (e.g., initializing and sustaining engagement, recruitment/retention).
• Develop and implement action plans that promote stakeholder-driven input and proposed actions to address the questions and improve the uptake of recommendations from research discoveries.
• Use of electronic health data from participants using data science to create predictive analytical models to understand strategies that predict health outcomes, including morbidity and mortality in pragmatic trials.
• De-implementation strategies that strengthen the adoption of evidence-based guidelines and practice targeted in the present study by decreasing or stopping low-value health care decisions.

The following types of applications will be considered nonresponsive to this NOSI and will not be reviewed:

• Applications in which the parent award is not an active R61/R33 or UG3/UH3 NHLBI Phase II-III clinical trial when the revision supplement application is submitted
• Applications in which the proposed timeline of the implementation study is incompatible with the established parent study timeline

Application Review Information

Review Criteria

The following review criteria will apply to all applications submitted in response to this NOSI. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

In addition, for applications involving clinical trials: 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.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scope

Reviewers will consider the appropriateness of the proposed expansion of the scope of the parent project and responsiveness to the purpose of this NOSI to incorporate implementation research on the diagnosis, prevention, and treatment of diseases and conditions of high priority to the NHLBI.

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

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?

In addition, for applications involving clinical trials:

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?

Investigator(s)

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?

In addition, for applications involving clinical trials:

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?

Innovation

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?

In addition, for applications involving clinical trials:

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?

Approach

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

In addition, for applications involving clinical trials:

Does the application adequately address the following, if applicable:

Study Design

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 NOSI: What is the likelihood that the proposed implementation research will lead to the ready uptake of the clinical study results from the parent study into clinical practice and real-world applications?

Environment

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?

In addition, for applications involving clinical trials:

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?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Study Timeline

Is the study timeline described in detail, considering start-up activities, the anticipated rate of enrollment, and planned follow-up assessment of the parent study? Is the projected timeline feasible and well-justified for the implementation research proposed considering the parent study's risks and benefits?

Specific to applications involving clinical trials:

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 the timing of overall recruitment/enrollment and retention goals for the implementation research within the context of the overall parent study timeline. The milestones must address 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 or UH3 phase to address the specific aims, and ensure the successful completion.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories 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.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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.

Vertebrate Animals

NIH staff will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: (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.

Biohazards

NIH staff 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.

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Select Agent Research

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).

Resource Sharing Plans

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).

Authentication of Key Biological and/or Chemical Resources

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.

Budget and Period of Support

NIH staff will consider whether the budget for the requested period of support are fully justified and reasonable in relation to the proposed research.

Application and Submission Information

Applications in response to this Notice must be submitted through PA-20-163, Competing Revisions to Existing NIH Grants and Cooperative Agreements (Clinical Trial Optional). All instructions in the SF424 (R&R) Application Guide and PA-20-163 must be followed, with the following additions:

• For funding consideration, applicants must include NOT-HL-20-795 in the Agency Routing Identifier field (Box 4b) of the SF424 (R&R) Form. Applications without this information in Box 4b will not be considered for this initiative
• Applications for revisions in response to this Notice must follow application instructions and be submitted on the following dates: November 23, 2020; November 23, 2021; and November 23, 2022 by 5pm at the local time of the applicant organization.
• Applications nonresponsive to the terms of this Notice will be not be considered for this initiative
• Investigators planning to submit an application in response to this NOSI are strongly encouraged to contact and discuss their proposed research with Program staff listed on this NOSI to determine appropriateness and interest of the NHLBI and to notify the program official of the parent study.

Personnel

• Necessary personnel for the proposed study submitted in response to this NOSI must have relevant expertise in implementation research and related fields. They should have well-documented past performance in the execution of implementation research.
• Revision applications must be submitted by the same project director/principal investigator (PD/PI), or Contact PD/PI for multi-PI grants, as listed on the current award. However, this NOSI encourages applicants to form new collaborations between implementation scientists working at different centers and with scientists that have expertise in varying disciplines. Collaborations are encouraged so that studies might jointly develop protocols and evaluate findings that inform effectiveness-implementation. Investigators should have a robust track record of funding in related areas, such as adherence, behavioral economics, predictive analytics, health systems, decision making, health services, comparative-effectiveness, and data analytics.

Research Strategy

• Provide a detailed description and rationale for the proposed implementation research hypothesis(es) and include how the project will address heart, lung, blood and/or sleep diseases and conditions and compliment the aims and research design of the existing parent study R33 or UH3 phase of the clinical trial using the bi-phasic (R61/R33 or UG3/UH3) NHLBI Phase II or III milestone-driven mechanism.
• Describe the rationale for choosing the selected implementation framework and methodology (quantitative, qualitative, or mixed-methods) and study design (e.g., pragmatic, adaptive, stepped-wedge, cluster-randomized, quasi-experimental, etc.). Describe expectations for the proposed implementation research to achieve the uptake of results from the parent study into clinical practice and real-world applications.

Critical Timelines

• Applications in response to this NOSI may be submitted as early as the R61 or UG3 phase for the time-sensitive start-up of the implementation research study close to the baseline, if appropriate. Applications are eligible for submission during the R33 or UH3 phase as long as the timeline is feasible for completing the study.

• Include a description and a table or graph of the overall study timeline that highlights key implementation research milestones. A project period of up to four years may be requested, with a justification of the time requested, including an efficient study timeline that leverages the parent study timeline and a milestone plan

Collection of New Information

• Applications submitted in response to this NOSI should address implementation research questions beyond those specified in the approved protocol of the parent study and are within the NHLBI's scientific mission. Applications should not be used to extend the parent study duration or provide funds solely for parent study enrollment, capitation, or study performance

Letters of Support

• Letters of support from the appropriate committee or person (e.g., Chair of the Steering Committee) are expected in response to this NOSI in order to demonstrate that there is adequate time remaining in the parent study to complete the proposed implementation science research as scientifically and technically appropriate. The letter(s) should indicate that the proposed implementation science will not interfere with the parent study or unduly burden participants, and clarify that all approved procedures and policies of the parent study will be followed. Suppose the proposed implementation science study extends beyond the project period of the parent study. In that case, the letter of support must include a commitment regarding the continuity of the collaboration and available resources beyond the parent study period of support. Applications that do not include letter(s) from the appropriate committee(s) or person(s) demonstrating the approval and cooperation of the parent study for the proposed implementation science research are considered incomplete and cannot be considered for this NOSI.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Keith Mintzer, PhD
National Institute of Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-7949
Email: mintzerk@nhlbi.nih.gov