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Guidelines for Investigator Initiated Multi-Site Clinical TrialsNational Heart, Lung, and Blood
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| Dates for receipt of Non-AIDS applications | Dates for receipt of AIDS applications | Assigned Council Round |
| August 17 - December 16 | October 8 - February 7 | May |
| December 17 - April 16 | February 8 - June 7 | October |
| April 17 - August 16 | June 8 - October 7 | January |
All applications that are a part of a cluster (i.e., submitted in response to PAR-10-096) must be eligible for continuous submission to be accepted under the alternative submission, referral, and review schedule shown above. If any application that is a part of cluster is not from a PI/MPI with continuous submission privileges, then all of the applications in the cluster must be submitted on-time according to the standard submission/receipt dates. If all the applications qualify for continuous submission then all the applications must be submitted at the same time. Please refer to the Frequently Asked Questions linked to NOT-OD-10-090 and located at http://cms.csr.nih.gov/ResourcesforApplicants/ContinuousSubmissionFAQ.htm for more information on this policy.
Foreign Organizations
Applications may be submitted from non-domestic (non-U.S.) entities (foreign organizations). NIH policies concerning grants to foreign organizations will apply (see http://odoerdb2.od.nih.gov/gmac/topics/foreign_main.htm).
D. SPECIAL INSTRUCTIONS FOR APPLICATIONS WITH $500,000 OR MORE IN DIRECT COSTS IN ANY YEAR
Requirement for separate Data Coordinating Center application
All multi-site randomized controlled trials with direct costs of $500,000 or more (excluding consortium F&A costs) in any year must include plans to submit at least two applications, one of which is for the support of a Clinical Coordinating Center (CCC) and the other which is for support of a Data Coordinating Center (DCC). The principal investigator for the DCC cannot be involved in (and cannot be a principal investigator on) any other award associated with the trial. For the purposes of peer review and funding, the Data Coordinating Center application and any other applications submitted as part of the same trial will be considered as a cluster, and each application will receive the identical cluster impact/priority score and summary statement.
Optional separate applications for core functions
Separate applications for core functions – e.g. reading centers, quality of life/economic analyses, imaging centers – may be submitted, but are not required. Separate applications for cores should only be submitted if it is scientifically and administratively more efficient and reasonable to have a separate grant award for the core function than, for example, to use a subcontract or fee-for-service agreement under the CCC or the DCC. Justification for separate core applications must be provided. The principal investigator for the core application cannot be involved in (and cannot be a principal investigator on) any other award associated with the trial. For the purposes of peer review and funding, the core application and any other applications submitted as part of the same trial will be considered as a cluster, and each application will receive the identical cluster impact/priority score and summary statement.
Requirement for NHLBI letter of approval to submit application for applications with direct costs of $500,000 or more
Applications for multi-site clinical trials with direct costs of $500,000 or more in any one year must follow NHLBI policy for applications requesting $500,000 or more in any year. (See http://www.nhlbi.nih.gov/funding/policies/500kweb.htm). Consortium or contractual facilities and administrative (F&A) costs do not count against the direct cost limit. The policy requires all applications that request direct costs of $500,000 or more in any year to be accompanied by a letter from NHLBI stating that it will accept the application. Note: The combined direct costs (excluding consortium F&A costs) of all applications in a multi-site clinical trial cluster must be considered when determining whether the application(s) require an NHLBI acceptance letter.
The procedures for obtaining an acceptance letter to submit an application in response to PAR-10-096 are described in the NHLBI over $500,000 policy document.
If multiple applications are submitted as part of a cluster, the acceptance letter from the NHLBI must be included as an attachment to the “PHS398 Cover Letter” component of the SF424 in each application.
E. USING THE SF424 (R&R) APPLICATION PACKAGE TO SUBMIT YOUR MULTI-SITE CLINICAL TRIAL APPLICATION
The SF424 Application has several components (also called forms). Detailed instructions for completing all parts of the SF424 forms can be found in the SF424 Application Guide (also see http://grants.nih.gov/grants/funding/424/index.htm). Applicants must follow the specific instructions for each component as described in the Application Guide. The components package associated with PAR-10-096 includes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:
Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Senior/Key Person
Research & Related Other Project Information
PHS398 Cover Letter File
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
Research & Related Budget
Optional Components:
Research & Related Subaward Budget Attachment(s) Form
Once the SF424 Application Package for PAR-10-096 is downloaded from Grants.gov, the application is built electronically by completing all the appropriate application components including attachments. The sections that follow highlight what key information about your clinical trial is required, and where it should be included in the SF424 Application. This section complements the complete, detailed instructions included in the SF424 Application Guide.
E.1. Title of Study
A brief descriptive title of the trial should be entered in item # 11 of the SF424 Cover Component. The title character length is limited to 81 characters, including the spaces between words and punctuation. Titles in excess of 81 characters will be truncated.
Multiple applications submitted as part of a cluster should use the same title on each application, plus a tag identifier at the end of each title to denote the function of the application. Commonly used tags for multi-site clinical trials include “Clinical Coordinating Center “ (“CCC”), “ Data Coordinating Center” (“DCC”), “Economics and QOL Core”, “Imaging Core”, etc. If one application is considered the lead application, this should be designated as part of the tag identifier. Titles, including tags, must not exceed the 81 character limit (or the system will truncate the excess characters).
Example of title with tag: “Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS) - CCC - Lead Application” (68 characters)
Trials with very long titles (i.e. more than 81 characters with tag) should use only an acronym plus the appropriate tag, and the full title should be spelled out in the abstract).
Example of long title with tag: “ALLHAT – DCC ” (acronym for “The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial – Data Coordinating Center”).A “new” application must have a different title from any other PHS project with the same PI. A “resubmission” (amended) application should have the same title as the previous application. A “renewal” (formerly called a competing continuation) application should have the same title as the currently funded grant, unless the specific aims have significantly changed, in which case a new title may be chosen.
E.2. Project Performance Sites
Listing multiple performance sites
All of the locations where the project will take place should be included in the “Research & Related Project/Performance Site Locations” component. Generally, the first site listed is the applicant institution, and is the primary, lead location where the project will be performed. As needed, other site(s) where the project will be performed, including other institutions, organizations, patient/subject enrollment sites, etc., should be listed in the blocks provided. If there are more than eight project/performance site locations, the information should be provided in a separate file, and then attached. Detailed instructions and a link to a sample Additional Performance Sites format page for greater than 8 locations are provided in the SF424 Application Guide.
Foreign sites
If the trial involves sites outside the United States or partnerships with international collaborators, or the applicant organization is a foreign institution, applicants must check “Yes” in item # 6 of the “Research & Related Other Project Information” form. The countries where the sites are located should be listed in item # 6a, and information on and justification of why the foreign site(s) have been chosen should be provided in item # 6b. Alternatively, applicants may provide information on why the foreign site(s) are being proposed in a separate file, and then attached next to Item 12 (Other Attachments) of the “Research & Related Other Project Information” form.
Capabilities, resources and experience of performance sites
In addition to listing collaborating institutions and enrollment sites in the “Research & Related Project/Performance Site Locations” component, the capabilities, resources, and experience of participating sites and centers related to the proposed trial should be described in sufficient detail. This information will be used by reviewers to assess the environment in which the proposed trial will be conducted. This information should be included in item # 10 (Facilities & Other Resources) of the “Research & Related Other Project Information” Component. Clinical, data management, laboratory, computer, equipment and other resources, should be described for performance sites. Only those resources that are directly applicable to the proposed work need be described. The applicant should thoroughly describe the structure and function of performance sites, and characteristics of the scientific environment in these sites that will contribute to the probability of success.
A separate file describing the resources, capabilities and experience of performance sites may be attached to item # 10 of the “Research & Related Other Project Information” component. Each performance site must have a scientific or medical director or PI, and the experience of each director must be documented. Letters of support from performance sites (and other collaborating institutions) should be provided with item # 14 of the “PHS398 Research Plan” component (see section E.11 below).
E.3. Investigative Team
The overall clinical trial must be directed by an investigator with experience in the conduct of clinical trials and expertise in the content area of the trial. The PI, and other key personnel (i.e., individuals who contribute in a substantive way to either the scientific development or execution of the project, such as co-investigators, project coordinators, consultants), should be well trained, have appropriate expertise, and demonstrable productivity. Such experience must be carefully documented. If the PI has not led a multi-site clinical trial before, it is advisable to include a senior person with such experience as a resource in the investigative team. Biographical sketches must be provided for all senior/key personnel and included in the “Research & Related Senior/Key Person Profile (Expanded)” component.
Biographical sketches of key personnel should be included in the “Research & Related Senior/Key Person Profile” component, following instructions in the SF424 Application Guide. The Biosketch should not exceed 4 pages in length. Biographical sketches should include a personal statement, positions and honors, selected peer-reviewed publications or manuscripts in press, and research support, Research support should include both selected ongoing and completed (during the last three years) research projects (Federal or non-Federal support), beginning with the projects that are most relevant to the research proposed in the application. Briefly indicate the overall goals of the projects and responsibilities of the key person identified on the Biographical Sketch. Do not include number of person months or direct costs. Do not confuse “Research Support” with “Other Support” as discussed in Part III of the SF424 Application Guide. Though they sound similar, these parts of the application are very different. As part of the biosketch section of the application, “Research Support” highlights your accomplishments, and those of your colleagues, as scientists. This information will be used by the reviewers in the assessment of each individual’s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. In contrast, “Other Support” information is required for all applications that are selected to receive grant awards and includes detailed financial information. NHLBI staff will request complete and up-to-date “other support” information from you after peer review. This information will be used to check that the proposed research is not already funded through other sources.
E.4. Study Organization and Administration
The organization of the study and how the trial will be managed must be described. An organizational chart showing the functions and relationships of the collaborating institutions, centers, sites, and any internal or external advisory committees, should be presented. The oversight, responsibilities, and coordination of any sites, centers or cores proposed must be discussed. A description of the role of any internal or external advisory committees (EAC), including the data and safety monitoring board (DSMB) must be included.
Note: In new or revised applications, EAC/DSMB members should not be named. Trials that are converted to Cooperative Agreements (U01s) will have a DSMB appointed by the NHLBI. In renewal applications (formerly called “competing continuation”) EAC/DSMB members already appointed may be named. New potential members should not be named.
When multiple PIs are proposed, NIH policy and instructions on multiple PIs should be followed (http://grants2.nih.gov/grants/multi_pi/overview.htm#format). For electronic applications, the special instructions in the Investigator Initiated Multi-Site Clinical Trials (R01) FOA should be followed.
The study organization and administration section should be included as an attachment to item # 12 (Other Attachments) of the “Research & Related Other Project Information” Component. The attached file should be named “Study Organization & Admin” to ensure it is bookmarked properly.
The application must describe any sub-contracts or service agreements for personnel or facilities and include a letter of support in the application.
A timetable for completion of the various stages of the trial must be included.
E.5. List of Clustered Applications for Clinical Trials with Direct Costs of $500,000 or More
For multiple applications submitted as part of a clinical trial cluster with combined direct costs of $500,000 or more in any year (excluding consortium F&A costs), a list of the clustered applications must be attached with item # 12 (Other Attachments) of the “Research & Related Other Project Information” Component. Each application must include an identical list of all the applications in the cluster, including for each the name of the PI and the applicant institution, and the title (including tag). The attached file should be named “List of Clustered Applications” to ensure it is bookmarked appropriately.
E.6. Cover Letter
For all applications submitted in response to PAR-10-096, a cover letter must be included in the “PHS398 Cover Letter” Component. The cover letter must include the name, institution, and contact information of the PI, the title of the trial (including any tag identifier), and, if the application is part of a cluster, the names and institutions of the PIs and the titles (including tags) of the other applications in the cluster. In each application in the cluster, an identical letter must be included.
If the application(s) have combined direct costs over $500,000 in any year (excluding F&A consortium costs), a letter from NHLBI showing approval to submit must be appended to the cover letter. The cover letter and appended NHLBI approval letter should be uploaded as one attachment to the “PHS398 Cover Letter” Component.
Additional information that may be required for the cover letter component is described in the SF424 Application Guide.
E.7. Projects awaiting FDA Approval, or Confirmation of Pharmaceutical Support, or Other Organization Support
If you are in the process of obtaining Food and Drug Administration (FDA) approval for an IDE, or an IND , or for amendments to an existing IDE or IND, details of the status of these negotiations and an expected timetable for their completion must be clearly described. Copies of memos to/from the FDA documenting the status of discussions must be provided if FDA approval is needed for the execution of the trial. This information should be attached to Item # 12 (Other Attachments) in the “Research & Related Other Project Information” component.
Similarly, if you are waiting for confirmation of financial or in-kind support from a pharmaceutical company, or another organization (e.g. professional association or society), the type/amount of support and timetable for confirmation of the support must be provided. This information - including letters of support from the organization - should be provided as an attachment to Item # 12 (Other Attachments) in the “Research & Related Other Project Information” component.
Key personnel on the study should also include in the “Research & Related Other Project Information” component of Item # 12 (Other Attachments) information on financial conflicts of interest that may exist.
E.8. Research Plan
The “PHS398 Research Plan” component of the SF424 is the scientific body of the application where the “research strategy” is presented. The Research Plan is designed to align the application with review criteria and present information in an organized manner to facilitate peer review. It includes sections for the introduction (if the application is a resubmission), specific aims of the study, significance, innovation, and approach, preliminary studies (for new applications), and an enrollment report (if the application is a renewal or revision), and a publication list (or progress report). A 1-page limitation exists for section 2 (Specific Aims) and a 12-page limitation exists for section 3 (Research Strategy) of this component. The “PHS398 Research Plan” also includes the Human Subjects sections, and other sections to describe applicable features of the study (see SF424 R&R Forms and Application Guide for specifics). The SF424 Application Guide suggests page lengths for individual sections of the “PHS398 Research Plan”.
The research strategy should include a clear description of the study design, study population, subject eligibility and inclusion/exclusion criteria, recruitment and enrollment plans, methods of randomization, primary and secondary endpoints and outcome measures, and treatment (including any follow-up procedures). Statistical methods should be appropriately matched to the study design and include sample size and power calculations, plans for data analyses, data management and quality control procedures.
For group randomized designs, an entire group (such as an entire clinic, school, etc.) is randomly assigned to the intervention or control/comparison condition. Studies with a group-randomized design should indicate eligibility and inclusion/exclusion criteria for the group to be randomized. Since data are collected on individuals who are in the randomized group, appropriate statistical approaches for the hierarchical nature of the data must be employed.
Specific Aims
State concisely the goals of the proposed research and summarize the expected outcome(s), including the impact that the results of the proposed research will exert on the research field(s) involved. The major research question, the study/target population, and hypothesis being studied should be clearly stated. The specific aims should specify the primary and major secondary endpoints to be measured, with a clear differentiation of the importance of each. Specific Aims are limited to one page.
Significance
The significance of the proposed clinical trial must be clearly stated. The application should make clear the need for the study with emphasis on how the results will advance our knowledge of theory and practice in this area. A discussion of the importance of the problem being studied (e.g., numbers of people affected, cost of care, quality of life, morbidity, mortality, etc.), the costs and benefits of the study, and the potential impact of the results of the trial should be included for evaluation of the trial's significance. It is particularly important that there be a discussion of how the trial will test the hypothesis proposed.
Innovation
Explain how the application challenges and seeks to shift current research or clinical practice paradigms.
Approach
The experimental approach should be based on a multi-site, randomized, controlled trial design The trial may randomize at the individual (patient) level or at a group level. The type of design, and rationale for the particular design chosen, should be described. There should be a clear description of the study population including the characteristics of this population and why it is an appropriate sample group to answer the research question(s) posed. A detailed list of subject eligibility and inclusion and exclusion criteria, or of group eligibility criteria for group-randomized trials, should be provided. A recruitment and enrollment plan, including a discussion of the availability of subjects for the proposed study, the ability of enrollment sites to recruit the required number of subjects, and the timeline for completion of recruitment, must be described. For group-randomized trials attention to recruitment of the groups as well as the subjects within the groups is needed. Approaches to be used for retention, cooperation and follow-up of subjects, and to address any anticipated changes in the composition of the study population over the course of the trial, should be described. Evidence supporting recruitment and retention projections (i.e. numbers of subjects, recruitment of women and minority subjects, time frame required) at the sites must be provided.
There should be a detailed description of the intervention to be tested and the randomization methods to be used to assign subjects (units) to either a control or experimental group. The clinical or behavioral protocol to be followed in each arm of the trial (i.e., intervention and control group protocols) must be provided, including all clinical, laboratory, physiological, and behavioral tests and procedures that will be used. A complete manual of operations is not required. Potential biases and approaches for minimizing bias should be described. The primary and secondary endpoints, and methods/measures to be used to assess these, should be clearly described. The link between endpoints, outcome measures, and hypotheses should be stated clearly. The research protocol and additional detailed information about measurement instruments, questionnaires, and data collection methods may be included in well-organized Appendices.
The sample size and power calculations and the underlying assumptions (and data) used to link the calculations to the endpoints, and to the hypotheses being tested, should be clearly described. Data collection plans and statistical methods appropriate for the particular design proposed should be presented. Methods to be used for data collection, preparation, management, quality control, and for ensuring blinding of study results (if applicable), should be thoroughly described. Procedures to ensure data confidentiality and subject privacy must be explained.
If a separate application for a DCC is included (as required for studies >$500K in direct costs in any one year), details of the randomization scheme, data collection, management, and quality control procedures, statistical analysis, blinding maintenance, and data confidentiality should be included in the DCC application.
Pilot Studies
The studies that led to the proposed clinical trial should be presented. Data from preliminary or pilot studies which show the need for and the feasibility of the trial should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified. 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. This information will also help to establish the experience and competence of the investigators to pursue the proposed project.
A timetable for completion of the various stages of the trial must be included.
Inclusion Enrollment Report
If the application is a renewal or revision application, a report on the enrollment of research subjects and their distribution by ethnicity/race and sex/gender must be included as an attachment to item # 4 (Inclusion Enrollment Report) of the “PHS398 Research Plan.” See SF424 Application Guide for instructions.
Progress Report Publication List
If the project was previously funded, a list of titles and complete references to all relevant publications, manuscripts accepted for publication, patents, and other printed materials that have resulted from the project must be included as an attachment to item # 5 (Progress Report Publication List) of the “PHS398 Research Plan.” See SF424 Application Guide for full instructions.
E.9. Human Subjects
Protection of Human Subjects
A Protection of Human Subjects section of the Research Plan is required for multi-site clinical trial applications. For applications submitted using the SF424 R&R instructions and forms, the information provided in the section on Protection of Human Subjects should be consistent with the information provided on the face page of the application. Applicants should refer to Part II of the SF424 Application Guide “Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan.”
The Scientific Review Group (SRG) will assess the adequacy of protections for research participants against research risks, and the appropriate inclusion of women, minorities, and children, based on the information provided in the application.
In the section on Protection of Human Subjects in the Research Plan, you must provide sufficient information for reviewers to determine that the proposed research meets:
1) The requirements of the DHHS regulations to protect human subjects from research risks (45 CFR Part 46). (See http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm). Assurances of the protection of human participants must be provided for the overall study and for individual performance sites. The applicant must discuss any issues which might lead to concern for the welfare of participants.
2) NIH policy requirements for Data and Safety Monitoring for Clinical Trials;
3) The ClinicalTrials.gov requirements if applicable;
4) The requirements of NIH policies on inclusion of women, minorities, and children (See http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm; http://grants.nih.gov/grants/guide/notice-files/not98-024.html); and
5) The requirements of NIH policy on reporting race and ethnicity data for subjects in clinical research.
NIH requires education on the protection of human research participants for all individuals identified in PHS applications as Senior/key Personnel who will be involved in the design or conduct of human subjects research, before funds are awarded for applications or contract proposals involving human subjects. For information relating to this requirement, see the following notices http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html and http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html, and Frequently Asked Questions at: http://grants.nih.gov/grants/policy/hs_educ_faq.htm.
Master templates of the forms to be used to obtain informed consent must be included either as an attachment to item # 6 (Protection of Human Subjects) in the “PHS 398 Research Plan” or as appendices (item # 16). Copies of individual enrollment sites’ informed consent are not required.
Data Safety and Monitoring
As of the October 2000, (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) applicants must include a Data and Safety Monitoring (DSM) Plan for all clinical trials that is commensurate with the risk level of the proposed clinical research. All applications or study protocols must include a general description of the monitoring plan, policies, procedures, responsible entities, and approaches to identifying, managing and reporting reportable events (adverse events and unanticipated problems), to the applicable regulatory agencies (e.g., Institutional Review Board (IRB), the NHLBI/NIH, the Office of Biotechnology Activities, Office of Human Research Protections (OHRP), the (FDA), and the Data and Safety Monitoring Board (if one is used). The NHLBI Data and Safety Monitoring Policy dated October 31, 2008 is described at www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm.
The DSM Plan must address the following areas:
- Who will manage and conduct the monitoring
- What will be monitored
- Proposed monitoring time points
- Where the monitoring will occur
- How the reportable events will be managed and reported
- How sites/centers, and participating facilities (labs, pharmacies) will be monitored?
NIH requires the establishment of Data and Safety Monitoring Boards (DSMBs) for Phase III multi-site clinical trials involving interventions that entail potential risk to participants (http://grants.nih.gov/grants/guide/notice-files/not98-084.html). The purpose of this board is to provide independent advice concerning scientific issues pertaining to subject safety and data quality. In monitoring the safety of the trial, the board also may recommend termination in the event of early significance of findings or the determination of unacceptable adverse effects or futility. The data and safety monitoring board is normally appointed in consultation with the NHLBI and consists of individuals who are not associated with the institutions participating in the trial.
Note: In new or resubmission applications, DSMB members should not be named. Trials that are converted to Cooperative Agreements (U01s) will have a DSMB appointed by the NHLBI. In renewal applications (“competing continuation”) EAC/DSMB members already appointed may be named. New potential members should not be named.
Women, Children and Minority Subjects Participation
Applicants should refer to Part II of the SF424 Application Guide “Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan.”
Targeted/Planned Enrollment Table
In addition to the written plans for the inclusion of women, minorities, and children in the proposed study, the composition of subjects must be provided using the "Targeted/Planned Enrollment Table" included in the SF424 Application Guide. This table should be attached to item # 10 (Targeted/Planned Enrollment) of the “PHS 398 Research Plan.”
Accrual Monitoring Plan
All clinical trials that plan to include 150 or more subjects need to adhere to the Guidance and Implementation for Monitoring Adequacy of Accrual of Participants to NHLBI Supported Human Subjects Research effective October 9, 2009 which is provided at http://www.nhlbi.nih.gov/funding/policies/accrual_guidelines.htm.
E.10. Consortium/Contractual Arrangements
Sub-contracts or service agreements for consultants, services, or recruitment sites, may be proposed. This information should be provided with item # 13 (Other Research Plan Sections) of the “PHS398 Research Plan.” Justification of the use of subcontracts or service agreements must be provided, as well as letters of support from the consortia/contractual partner(s).
E.11. Letters of Support
Letters of support are required from all individuals serving as consultants; from all organizations, centers, and institutions providing services, support or resources; organizations providing financial or in-kind resources (e.g., pharmaceutical companies); and from enrollment centers or sites contracted to enroll study subjects. Letters should confirm their commitment, roles in the project and rate/charge for consulting services. Letters should be signed by business officials or medical directors of the organizations/sites. Letters of support should be attached to item # 14 (Letters of Support) in the “PHS 398 Research Plan.”
E.12. Appendices
Data collection forms, questionnaires, and other complementary materials that provide further details of the protocol and data analysis methods should be included in well organized appendices in the “PHS 398 Research Plan” component.
Note: NIH has published new limitations on grant application appendix materials to encourage applications to be as concise as possible while containing the information needed for expert scientific review. Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).
The Appendix should not be used to circumvent the 12 page limitations of section 3 (i.e., Research Strategy) of the “PHS398 Research Plan” component.
F. BUDGET
All applications must provide detailed scientific and operational plans as well as funding needs for the entire trial and data analysis period, even if this period exceeds five years. The review of the application will evaluate the entire project. The Institute commitment will be mindful of this total project need although the award period may be for less time.
Investigators must submit a total overall budget and a complete, justified, individual budget for each year of support requested. The SF424 Application Guide has detailed instructions on filling in budget pages. All costs requested and all changes in budgets after the first year should be clearly identified and justified. If part of the costs of the trial is to be borne by sources other than NIH, these contributions must be presented in detail along with supporting letters signed by individuals who have the authority to make fiduciary commitments on behalf of the institution.
Special Instructions for projects requesting more than 5 years of funding:
Most multi-site clinical trials request funding for 5 years or less. In rare cases, a study may require longer funding. The SF424 R&R budget component does not easily accommodate more than 5 years at this time. Therefore, if you are preparing a budget for more than 5 years, follow these special instructions:
- For the Project Period (Item # 12 in the “Research & Related Cover” component) show all years. For the total Estimated Project Funding (item # 15 in the Research & Related Cover” component) show the total of all years’ costs.
- For the detailed budget (“Research & Related Budget” component) complete the detailed budget for years 1-5. Include the same level of detail for Years 6 (and beyond) in the Budget Justification (section K of the “Research & Related Budget” component) along with an explanation of this unique situation.
- With your cover letter (“PHS398 Cover Letter” component) attach a letter that addresses this unique > 5 year feature.
- PHS398 Checklist/Program Income: If any Program Income amounts are anticipated in Years 6 or beyond, include the information as part of the Year 5 budget period in Item # 4 (Program Income) of the “PHS398 Checklist” component, and provide clarity in the “Sources” text section.
- This approach may generate a warning about the Project Period > 5 years; however, it is a warning that you will have addressed already in the Cover Letter.
Subcontracts
Separate itemized budgets must be prepared for each subcontract and/or for each collaborating center or core, if multiple centers or cores are proposed. These budgets should be prepared using the R&R Sub award Budget Attachment Forms in the SF424.
For applications under consideration for funding, NHLBI will request "Just-in-Time" information from the applicant. For details, applicants may refer to the SF424 Application Guide, Version 2-III, section 1.8 (Other Support) or NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General [http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm]
Further information concerning budget preparation may be obtained from the Director, Office of Grants Management, DERA, NHLBI.
G. FORMAT OF MULTIPLE APPLICATIONS SUBMITTED AS PART OF A CLUSTER
All multi-site randomized controlled trials with direct costs of $500,000 or more (excluding consortium F&A costs) in any year must include plans to submit at least two applications, one of which is for the support of a DCC. Separate applications for core functions – e.g., reading centers, quality of life/economic analyses, imaging centers – may also be submitted, but are not required. For the purposes of peer review and funding, the DCC application and any other applications submitted as part of the same trial will be considered as a cluster, and each will receive the same priority score and summary statement.
Each application submitted as part of a cluster must be in response to FOA PAR-10-096 and submitted using the SF424 electronic application package by the intended receipt date. In addition, the following guidelines should be followed:
- Each application must have the same base title, plus a Tag at the end of the title, indicating the role of the application (e.g., DCC)
- Each application must submit an identical cover letter which lists the names of the PIs, institutions, and titles (including Tags) of other applications in the cluster
- Each application’s cover letter should have attached a copy of the NHLBI approval letter
- Each application must have the same abstract attached to item # 7 (Project Summary/Abstract) of the “Research and Related Other Project Information” component and the same short narrative attached to item # 8 (Project Narrative) of the “Research and Related Other Project Information” component
- Each application must include only its own budget, including any subaward budgets associated with it
- Each application must include only its own personnel and respective biographical sketches
- Each application must include only its own letters of support, appendices, and other attachments
- Each application must include only information pertinent to its own applicant institution and PI in its checklist
Generally, the lead application in a cluster is from the organization/institution where the main PI is located, and which will provide overall scientific and clinical management. Frequently this application is called the “Clinical Coordinating Center” (CCC). The Data Coordinating Center DCC (DCC) application is from the organization/institution that provides leadership in all statistical and data coordination aspects of the trial. For the Research Plan components of these applications, the following guidelines should be followed:
- The lead application (usually the CCC) must contain the specific aims, background and significance, preliminary studies, research design and methods, inclusion enrollment report and progress report publication list (if appropriate) sections of the “PHS398 Research Plan” component. The Research Strategy section should include a clear description of the trial design, primary and secondary endpoints, subject eligibility, inclusion/exclusion criteria, recruitment and enrollment plans. Briefly address study power, sample size, and main statistical methods to be used. However, the entire details of the data collection, entry, management, coordination, randomization, and analytical procedures should not be included in the CCC application. These details should be included in the DCC application.
- The DCC should reiterate the same overall study goals as the CCC application. It should also list specific aims and function of the DCC. The DCC application need not repeat the background and significance section contained in the CCC application, but may include an abbreviated version of this, and a reference to the corresponding section in the CCC application. Similarly, the DCC application need not repeat verbatim the approach section of the CCC application, but should, instead, present an abbreviated synopsis of what was contained in the CCC application (with a reference to the section in the CCC application) and more detail on the data management and statistical aspects of the trial. This is the appropriate place to discuss details of the randomization scheme, power analysis and sample size justification, details of data management procedures, systems, quality assurance, training and certification, details of statistical analyses and tests to be used, etc.
All applications submitted as part of a cluster will be reviewed by the same panel. Review panels will include expertise in biostatistics and appropriate clinical and behavioral trial approaches.
Applications other than the CCC and DCC submitted as part of the cluster – such as cores, reading centers, quality of life/economic analyses – should follow the same principles as those outlined for the DCC. That is, the focus of the research design and methods section should be on the rationale for and function of the core only.
The Research Strategy of CCC and DCC applications are limited to 12 pages for section 3 of the “PHS398 Research Plan” component. Applications for core functions should not exceed 6 pages for the Research Strategy.
H. INSTITUTE STAFF INVOLVEMENT
Before making an award for an Investigator-Initiated Clinical Trial, NHLBI will routinely consider the desirability of substantial continued staff involvement in a supportive role. If such involvement is deemed appropriate by the Institute, the award mechanism will be a cooperative agreement (U01). Regardless of the mechanism of support, the NHLBI staff will closely monitor progress during the award. This monitoring will include submission of the IRB approved protocol to the NHLBI Program Official, adequate monitoring of serious adverse event management and reporting, adequate accrual monitoring plans, and regular communications with the principal investigator and staff, as well as attendance at the steering committee, data and safety monitoring board, and related meetings. The Terms and Conditions for an award for a clinical trial will include recruitment milestones expected to be met by the study as a whole at specific time periods, accrual goals for women and minorities (as appropriate), any requirements regarding minimum effort of specific key personnel, and any other identified requirements for completion of the approved research. As with any award, continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NHLBI will consider ending support and negotiating a phase-out of the award (http://www.nhlbi.nih.gov/funding/policies/accrual_guidelines.htm). The NHLBI retains, as an option, periodic external peer review of progress.
I. REPORTING REQUIREMENTS
Recruitment progress (including recruitment of women, children and specific minority groups), indices of quality control, and related operational features must be reported at regular intervals to the NHLBI program office. Annual and final reports are required as in any grant.
J. NHLBI REVIEW OF APPLICATIONS
All applications for multi-center clinical trials involving a randomized clinical or behavioral intervention and assigned to the NHLBI, undergo primary technical review by the Clinical Trials Review Committee (a standing review committee) or, more rarely, a similar ad hoc Special Emphasis Panel (SEP) managed by the NHLBI's Division of Extramural Research Activities. As with any other grant application, the application will be assigned to the appropriate NHLBI Division and Program for scientific administration and management.
As part of the initial merit review, all applications will:
- Undergo a selection process in which applications will be discussed and assigned a impact/priority score. Applications may undergo streamlined review.
- Receive a written critique.
- Receive a second level of review by the NHLBI National Advisory Council.
Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:
- Scientific merit of the proposed project as determined by peer review.
- Availability of funds.
- Relevance to program priorities.
The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
Overall Impact. Reviewers will provide an overall impact/priority 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 five core review criteria, and additional review criteria (as applicable for the project proposed).
Scored Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical 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. Each of the core review criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application.
Significance: Does the project address an important problem or a critical barrier to progress in the field? 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?
Investigators: Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, 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? Are the responsibilities of key staff members well-suited to their expertise? Is the effort of the staff member commensurate with the responsibilities involved? Do the clinical centers employ the appropriate personnel to recruit subjects and implement the clinical protocol? Does the application(s) involve the appropriate personnel to ensure appropriate coordination, data management (including quality control), and regulatory and statistical/analytical support?
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?
Approach: Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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? If the project involves clinical research, are the plans for (1) protection of human subjects from research risks, and (2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Is the planned recruitment timeline feasible? Is there a plan to monitor accrual? Is the primary endpoint adequately powered and appropriate to test the research question? Are data management and quality control procedures adequate? Are planned analyses appropriate for the proposed study design?
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? Is there evidence of institutional support? Are facilities and resources available for the research project adequate? For multicenter applications, is there evidence of the ability of the individual centers 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 CRITERIAM
As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.
Organization: Is the proposed organizational structure appropriate? What impact does the organizational structure have on the scientific goals of the project? What is the quality of the DSM Plan to monitor sites/centers, and participating facilities (labs, pharmacies)?
Protections for Human Subjects. For research that involves human subjects but does not involve one of the six 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 six 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.
Adequacy of Data and Safety Monitoring (DSM) Plan. DSM plan is commensurate with the risk level of the proposed clinical research, includes adequate description of the monitoring plan, policies, procedures, responsible entities, management and reporting of the reportable events, both adverse events and unanticipated problems, to the applicable regulatory agencies (e.g., Institutional Review Board (IRB), the NHLBI/NIH, the Office of Biotechnology Activities, Office of Human Research Protections, and the Food and Drug Administration). The NHLBI Data and Safety Monitoring Policy is described at www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm.
The DSM Plan must address the following areas:
- Who will manage and conduct the monitoring?
- What will be monitored?
- Proposed monitoring time points?
- Where the monitoring will occur?
- How the reportable events will be managed and reported?
Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.
Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: (1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; (2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; (3) adequacy of veterinary care; (4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and (5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia.
Resubmission Applications. When reviewing a Resubmission application (formerly called an amended application), 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.
Renewal Applications. When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.
Revision Applications. When reviewing a Revision application (formerly called a competing supplement application), 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.
Biohazards. 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.
ADDITIONAL REVIEW CONSIDERATIONS
As applicable for the project proposed, reviewers will address each of the following items, but will not give scores for these items and should not consider them in providing an overall impact/priority score.
Applications from Foreign Organizations. Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
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 (http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).
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).
Budget and Period Support. Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research. All applications must include plans for adherence of NIH policies for:
- Data sharing (for applications seeking $500,000 or more in direct costs in any one year)
- Access to Research Data through the Freedom of Information Act
- NIH Public Access
Applicants should refer to FOA PAR-10-096 (http://grants.nih.gov/grants/guide/pa-files/PAR-10-096.html) or SF424 (R&R) Application Guide (http://grants.nih.gov/grants/funding/424/index.htm) for specific information and instructions regarding these policies.
K. CONTACTS FOR FURTHER INFORMATION
Director, Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 8128
Bethesda, Maryland 20892-7940
(301-435-0466)
Director, Division of Lung Diseases
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 10138
Bethesda, Maryland 20892-7952
(301-435-0233)
Director, Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 9136
Bethesda, Maryland 20892-7950
(301-435-0080)
Scientific Review Officer
Clinical Trials Review Committee
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 7194
Bethesda, Maryland 20892-7924
(301-435-0288)
Last Updated May 2011
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