Guidelines for Investigator Initiated Multi-Site Clinical Trials

National Heart, Lung, and Blood Institute
National Institutes of Health

Revised: April 2009

A. PURPOSE OF THIS DOCUMENT

This document outlines National Heart, Lung, and Blood Institute (NHLBI) policy and procedures for investigator-initiated, multi-site, randomized, controlled clinical trial grant applications. It provides guidelines for the preparation, format and submission of these applications. It explains the requirements of receipt, review, and funding of applications for multi-site clinical trials. This is not a solicitation for applications.

These guidelines are designed specifically for applications that will be assigned to the Clinical Trials Review Committee (CLTR) or, more rarely, a similar ad hoc Special Emphasis Panel (SEP) convened by the NHLBI, for initial merit review. They are not designed for investigator-initiated single-site randomized controlled trials, or multi-site observational studies that are not testing an intervention with a randomized design.

For applications submitted electronically (see section C, below) this document is intended to complement, and should be used in conjunction with, Funding Opportunity Announcement (FOA) Program Announcement (PA) Number: PAR-07-373 “Investigator-Initiated Multi-Site Clinical Trials (R01)” (http://grants.nih.gov/grants/guide/pa-files/PAR-07-373.html),  

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B.  SCOPE

These guidelines pertain to investigator-initiated multi-site, randomized, controlled clinical trials.Investigators are encouraged to read the NHLBI’s clinical research guide at http://www.nhlbi.nih.gov/crg/index.php for definitions (and additional resources) related to clinical research.  Applications may address any research question related to the mission and goals of NHLBI and may involve clinical or behavioral interventions. 

The proposed research must address a scientifically important question, must provide valuable information to the existing knowledge base, and must have public health relevance. Research topics should be based on the NHLBI’s national program plan areas of heart, lung, and blood diseases, and sleep disorders. Information about the program areas and strategic plan of the NHLBI may be found at NHLBI’s website (http://www.nhlbi.nih.gov/index.htm). 

For the purposes of these guidelines a multi-site randomized controlled clinical trial is characterized by the following:

• Study subjects are recruited from two or more geographically distinct enrollment sites, or centers.  The sites are distinct in demographic, socioeconomic, clinical or other characteristics. 
• A clinical or behavioral intervention is being tested using a randomized trial design.  That is, individual subjects or clusters are randomly assigned to receive a clinical or behavioral intervention or to serve as a control.
• The trial may randomize at the individual (patient) level or at a group or “cluster” level (e.g., randomization of clinics, schools, worksites, etc.).
• Subject screening, recruitment, and the study protocol are conducted at the enrollment sites.   
• Clinicians/staff at each site are trained to implement the protocol. 

NHLBI uses the Research Project Grant (R01) or Cooperative Agreement (U01) award mechanism to support investigator initiated multi site clinical trials.  Pending awardees will be notified if the proposal will be awarded as a U01.   “Just-in-Time” information concepts will also be applied.

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C.  APPLICATION AND SUBMISSION INFORMATION

All new, resubmission (formerly “revised” or “amended”), and revision (formerly “competing supplement”) applications seeking support from NHLBI for investigator initiated multi-site randomized controlled trials must be submitted electronically.    Such applications must be prepared in response to Funding Opportunity Announcement (FOA) Program Announcement (PA) Number: PAR-07-373 “Investigator-Initiated Multi-Site Clinical Trials (R01)” (http://grants.nih.gov/grants/guide/pa-files/PAR-07-373.html). 

Applications prepared in response to PAR-07-373 must be submitted using the SF424 Research and Related (R&R) forms and the SF424 R&R Application Guide, through Grants.gov (http://www.grants.gov/ ).  To download a SF424 R&R Application Package for FOA PAR-07-373, click on “Apply for Grant Electronically” on page 1 of the FOA.

Renewal (formerly “competing continuation”) applications that have been funded as Cooperative Agreements (i.e. using the U01 mechanism) must be submitted using the PHS398 Grant Application (http://grants.nih.gov/grants/funding/phs398/phs398.html).   

All applications (electronic and paper) must follow standard NIH submission policies (http://grants.nih.gov/grants/funding/submissionschedule.htm#policy).

• Receipt dates

Standard submission/receipt dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm.

• Multiple applications submitted as a cluster

When two or more applications are submitted as part of the same multi-site clinical trial, they are considered a “cluster” for the purposes of peer review and funding.  Each application in the cluster must be prepared in response to PAR-07-373 and each application must be submitted electronically using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide through Grants.gov.

• Multiple Principal Investigators

More than one Principal Investigator (PI), or multiple PIs, may be designated on an application.   NIH multiple PI’s policy will apply (see  http://grants2.nih.gov/grants/multi_pi/).  Applications must be prepared in accordance with NIH multiple PI policy and, for electronic applications, following special instructions in PAR-07-373.

• 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).

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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 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 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 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 FOA PAR-07-373 are described in the NHLBI over $500,000 policy document.    

If multiple applications are submitted as part of a cluster, and the applications are submitted electronically, the acceptance letter from the NHLBI must be included as an attachment to the “PHS398 Cover Letter” component of the SF424 in each application.   If the applications are submitted using the PHS398 paper format (i.e. for cooperative agreement renewals), the acceptance letter must be included with the cover letter accompanying each application.

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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 FOA PAR-07-373 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 Profile (Expanded)
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 FOA PAR-07-373 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: “Perioperative Cardiac Event Trial (PROTECT) – CCC – Lead Application” (59 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: “HF-ACTION – DCC ” (acronym for “The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial – Data Coordinating Center”).

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 # 5a of the “Research & Related Other Project Information” form.  The countries where the sites are located should be listed in item # 5b, and information on and justification of why the foreign site(s) have been chosen should be provided in item # 5c.  Alternatively, applicants may provide information on why the foreign site(s) are being proposed in a separate file, and then attached next to Item 11 (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 # 9 (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 # 9 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 # 11 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.  Biographical sketches should include 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. 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 has not already been Federally-funded. 

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 resubmission applications (“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 PAR-07-373 should be followed.

The study organization and administration section should be included as an attachment to item # 11 (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 # 11 (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 FOA PAR 07-373 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 # 11 (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 # 11 (Other Attachments) in the “Research & Related Other Project Information” component.

E.8.  Research Plan

The “PHS398 Research Plan” component of the SF424 is the scientific body of the application where the research plan is presented.  This component is designed to present information in an organized manner and to facilitate peer review.   It includes sections for the introduction (if the application is a resubmission or revision), specific aims of the study, background and significance, relevant preliminary studies, research design and methods, an enrollment report (if the application is a renewal or revision), and a publication list (or progress report).    A 25-page limitation exists for sections 2 (Specific Aims) through 5 (Research Design and Methods) 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 plan 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 (also called “cluster randomized trials”), 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

The broad, long-term objectives and the goals (specific aims) of the research proposed should be included in the specific aims section.  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.   

• Significance and Background

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.

• Preliminary 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.

• Research Design and Methods

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 or (cluster) 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) should be described, 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.   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.

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 # 6 (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 # 7 (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 # 8 (Protection of Human Subjects) in the “PHS 398 Research Plan” or as appendices.   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).  Therefore, 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 revised applications, DSMB members should not be named.  Trials that are converted to Cooperative Agreements (U01s) will have a DSMB appointed by the NHLBI. In resubmission 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.” 

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 # 15 (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 # 16 (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 25 page limitations of sections 2-5 of the “PHS398 Research Plan” component.

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