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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).
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.
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”). A “new”
application must have a different title from any other PHS
project with the same PI. A “revision” or “resubmission”
(amended) application should have the same title as the
previous application. A “renewal” (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.
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.
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.
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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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 # 13 in the “Research
& Related Cover” component) show all years. For
the total Estimated Project Funding (item # 16 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.
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.
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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-07-373 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 # 6 (Project Summary/Abstract) of the “Research
and Related Other Project Information” component and the
same short narrative attached to item # 7 (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 design and methods section should include a clear
description of the trial design, study power, sample size, and
main statistical approaches 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
objectives 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 research
design and methods section that were included in 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, 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.
CCC applications are limited to 25 pages for sections 2-5
of the “PHS398 Research Plan” component. It is
recommended that DCCs be no more than 15 pages for sections
2-5, although up to 25 pages is permitted. Cores should
be no more than 5 pages for sections 2-5.
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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, 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. The NHLBI retains, as an
option, periodic external peer review of progress.
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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.
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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 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 of program priorities.
The goals of NIH supported research are to advance our
understanding of biological systems, to improve the control of
disease, and to enhance health. In their written critiques,
reviewers will be asked to comment on each of the following
criteria in order to judge the likelihood that the proposed
research will have a substantial impact on the pursuit of
these goals. Each of these criteria will be addressed and
considered in assigning the overall score, weighting them as
appropriate for each application.
- Significance
- Approach
- Innovation
- Investigator
- Environment
Note that an application does not need to be strong in all
categories to be judged likely to have major scientific impact
and thus deserve a favorable priority score. For example, an
investigator may propose to carry out important work that by
its nature is not innovative but is essential to move a field
forward. Reviewers receive the following guidance
regarding criteria:
Significance: Does
this study address an important problem? If the aims of the
application are achieved, how will scientific knowledge or
clinical practice be advanced? What will be the effect of
these studies on the concepts, methods, technologies,
treatments, services, or preventative interventions that drive
this field?
Approach: Are the
conceptual or clinical framework, design, methods, and
analyses adequately developed, well-integrated, well-reasoned,
and appropriate to the aims of the project? Does the applicant
acknowledge potential problem areas and consider alternative
tactics? For applications designating multiple PDs/PIs, is the
leadership approach, including the designated roles and
responsibilities, governance, and organizational structure,
consistent with and justified by the aims of the project and
the expertise of each of the
PDs/PIs?
Innovation: Is the project
original and innovative? For example: Does the project
challenge existing paradigms or clinical practice; address an
innovative hypothesis or critical barrier to progress in the
field? Does the project develop or employ novel concepts,
approaches or methodologies, tools, or technologies for this
area?
Investigators: Are the PD/PIs
and other key personnel appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to
the experience level(s) of the principal investigator(s) and
other researchers? Do the PD/PIs and investigative team bring
complementary and integrated expertise to the project (if
applicable)?
Environment: Do(es) the
scientific environment(s) in which the work will be done
contribute to the probability of success? Do the proposed
studies benefit from unique features of the scientific
environment(s), or subject populations, or employ useful
collaborative arrangements? Is there evidence of institutional
support?
For the initial review of any Data
Coordinating Centers or Core Facilities the same criteria will
be used.
All applications undergo further review by the
National Heart, Lung, and Blood Advisory Council prior to
award. The purpose of this review is to consider the trial in
the context of the overall program plans and planning
activities of NHLBI. These recommendations reflect such
factors as program priority, program balance, cost, and cost
benefit of the trial. The Council is responsible for the
second level of review and makes recommendations to the
Director of the NHLBI regarding funding.
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K.
ADDITIONAL REVIEW CONSIDERATIONS
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)
- Research resources sharing
- Model organism sharing
- Access to Research Data through the Freedom of
Information Act
- NIH Public Access
Applicants should refer to FOA PAR-07-373 (http://grants.nih.gov/grants/pa-files/PAR-07-373.html)
or SF424 (R&R) Application Guide (http://grants.nih.gov/grants/funding/424/index.htm)
for specific information and instructions regarding these
policies.
L. CONTACTS FOR
FURTHER INFORMATION
Director, Division of Cardiovascular Diseases 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)
Director, Division of Prevention and Population
Sciences National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 10122 Bethesda, Maryland
20892-7938 (301-435-0422)
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)
Director, Office of Grants Management National Heart,
Lung, and Blood Institute Rockledge 2 Building, Room
7154 Bethesda, Maryland 20892-7926 (301-435-0166)
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