Guidelines for
Investigator Initiated Clinical Trials
National Heart, Lung, and Blood Institute
National Institutes of Health
Revised: September 2003
A. PURPOSE OF THIS DOCUMENT
This document outlines National Heart, Lung, and Blood Institute
(NHLBI) policy and procedures for Investigator-Initiated Clinical
Trials and provides guidelines for the preparation and submission
of these applications. It lists the requirements placed on
the receipt, review, and funding of these applications and
presents guidelines for the conduct of such trials. This is
NOT a solicitation for such applications.
B. INSTITUTE ACCEPTANCE OF APPLICATIONS
Applications for support of Investigator-Initiated Clinical
Trials must be submitted to NIH through its Center for Scientific
Review (CSR). In December 1993, NIH advised potential applicants
of investigator-initiated research grants of $500,000+ in
direct costs in any year to contact Institute staff early
in the development of their application. As of June 1996 all
new investigator initiated research grants exceeding $500,000
in any year are required to include a letter indicating that
the application has been discussed with Institute staff who
are willing to accept the application. Notice was given that
FAILURE TO CONTACT INSTITUTE STAFF MAY RESULT IN THE APPLICATION
BEING RETURNED WITHOUT REVIEW. Since most multicenter
clinical trials fall under this guidance, applicants must
contact Institute staff to discuss any new, renewal, or supplemental
application to seek review and assistance in the preparation
of their application(s). This review will assess programmatic
priority based on the consideration of anticipated program
needs and balance as well as costs and budgetary constraints.
Additional information on the $500,000+ policy can be found
at : http://www.nhlbi.nih.gov/funding/policies/500kweb.htm.
All multicenter applications, involving an 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 Affairs. Most
single center applications and multicenter applications without
an intervention undergo primary technical review by the appropriate
study sections in the Center for Scientific Review. As with
any other grant application, the application will be assigned
to the appropriate NHLBI Division and Program for scientific
administration and management.
All clinical trial applications must be received on one
of the following receipt dates: February 1, June 1, or October
1. These dates apply to revised and renewal applications as
well as new applications.
C. APPLICATION FORMAT
The standard PHS 398 Rev. 5/01, Grant Application Form, is
used to apply for Investigator-Initiated Clinical Trials.
Investigators should generally adhere to the guidelines detailed
in the PHS 398 application kit. Any exceptions must be specifically
authorized by the Scientific Review Administrator of the Clinical
Trials Review Committee at the address listed in section I
of this document. Materials required for review will vary
according to whether the trial is referred to NHLBI or CSR
for review.
Clinical trials often require the collaboration of multiple
field centers, and may include separate data coordinating
centers and core facilities. The need for separate centers
and cores must be carefully and completely described and justified.
Separate budget justifications, facility statements, and informed
consent forms must be submitted for each center. Commitment
from the principal investigators and business offices of each
center must be documented. The choice of mechanism for support
of multiple centers, consortia or single awards to multiple
centers, will be made during the consultation with Institute
staff.
The information provided in the application should be organized
in a manner that will facilitate peer review. The body of
the application must present an overview of the state of the
science, current status and relevance of the trial, a discussion
of the specific protocol, and the approach to data collection
and analysis. It is recognized that this 25-page overview
does not permit adequate detail for a complete review of the
study. Therefore, details of the protocol, methods, quality
control procedures, power analysis, data analysis, and similar
material should appear, when needed for a thorough discussion,
in well organized and referenced appendices.
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,
itemized individual budget for each year of support requested.
Separate itemized budgets must be prepared for each subcontract
and/or for each center or core for each year, if multiple
centers or cores are proposed. All costs requested and all
changes in budgets after the first year should be clearly
identified and justified. Further information concerning budget
preparation may be obtained from the Chief, Grants Operations
Branch, DEA, NHLBI
The following sections must be included in the grant application:
o Specific Aims
The specific aims of the trial must be clearly and concisely
presented. These should include a clear specification of the
primary and major secondary endpoints to be measured, with
a clear differentiation of the importance of various endpoints.
o Significance
The significance of the proposed clinical trial must be clearly
stated. It is particularly important that there be a discussion
of how the trial will test the hypothesis proposed. 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 costs and benefits of the
study should be included for evaluation of the trial's significance.
o Preliminary Studies
The studies that led to the proposed clinical trial should
be presented. Data from 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.
THE INSTITUTE DOES NOT ACCEPT, REVIEW, OR FUND PILOT STUDIES.
A PILOT STUDY IS ONE WHOSE MAJOR PURPOSE IS TO DEMONSTRATE
THE FEASIBILITY OF FURTHER STUDIES.
o Experimental Design and Methods
1. Detailed Clinical Protocol
List the inclusion and exclusion criteria and describe the
procedure to be utilized for assignment of patients to experimental
conditions. Discuss in detail the study design for the intervention(s)
to be used, including the rationale for the particular design
chosen and procedures to assure compliance with, and standardized
implementation of, the proposed protocol. Discuss potential
biases in the research protocol proposed and how they will
be addressed. Clinical (including behavioral), laboratory,
and physiological tests and protocols should be described
briefly here and in more detail in an appendix. Methods of
randomization must be described and endpoints clearly defined.
Assumptions and steps used to arrive at the proposed sample
size must be described. Details of the sample size calculations
should be presented in an appendix.
2. Patient Availability and Recruitment
Discuss the availability of patients for the proposed study.
Discuss the characteristics of this population and why it
is an appropriate group to answer the question posed. Outline
the approaches to be utilized for the recruitment, retention
and follow up of the required number of patients. Discuss
plans for maintaining the cooperation of the study population
as well as plans for addressing any anticipated changes in
the composition of the study population over the course of
the trial. Data should be presented supporting recruitment
and retention estimates. The ability of clinical centers to
recruit and retain the proposed number of subjects, including
women and minority subjects, must be addressed.
3. Data Management, Quality Control, and Data Analysis
Describe the approach to data management. Include methods
for monitoring the quality and consistency of the intervention(s)
and data collection. Include prototypes of data collection
forms in an appendix. Provide at least an outline of the Manual
of Operations. Describe the methods of data analysis, linking
the analyses to the hypotheses to be tested. Include methods
of data preparation and presentation, analytic methods, and
approaches to data synthesis. Primary and secondary endpoints
should be clearly defined, justified and related to the power
calculations.
o Human Subjects
As of October 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html),
NIH implemented a policy requiring education on the protection
of human research participants for all key personnel submitting
applications for grants or proposals for contracts or receiving
new or non-competing awards for projects involving human research
participants.
Assurances of the protection of human participants and the
biohazard safety of employees (if applicable) must be provided
both for the overall study and for individual field centers.
The applicant must discuss any issues which might lead to
concern for the welfare of participants. All forms to be used
to obtain informed consent AT EACH CENTER must be included
in an appendix. At a minimum, the human subjects sections
of data coordinating center applications must address data
security measures and confidentiality. (See PHS Form 398 for
detailed instructions concerning content of the human subjects
section of the application).
o Women, Children and Minority Subjects and Minority Institution
Participation
It is the policy of the NIH that women and members of minority
groups and their sub-populations must be included in all NIH-supported
biomedical and behavioral research projects involving human
subjects, unless a clear and compelling rationale and justification
are provided indicating that inclusion is inappropriate with
respect to the health of subjects or the purpose of the research.
This policy results from the NIH revitalization Act of 1993
(Section 492B of Policy Law 103-43). All investigators proposing
research involving human subjects should read the UPDATED
"NIH Guidelines for Inclusion of Women and Minorities as Subjects
in Clinical Research, published in the NIH Guide for Grants
on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at:
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
Other relevant documents may found at: http://grants.nih.gov/grants/funding/women_min/women_min.htm
.
A SEPARATE section of the application should include the
following: The literature and/or data sets must be reviewed
to indicate to the extent possible (a) the distribution, by
gender and minority status, of the US population with the
disease or health problem under investigation and (b) whether
the impact of the intervention may be expected to vary according
to gender or minority status. Specific goals for women and
minority recruitment and plans for achieving those goals must
be explicitly stated. Approximate percentages of women and
each minority group expected in the study sample and the basis
for these estimates must be provided. Generally, representation
of women and minorities will not be considered adequate unless
they occur in the study population in the same proportions
as in the U.S. population having the disease entity being
studied. Outreach and/or sampling plans to ensure adequate
gender and minority representation must be presented. Past
track records in recruitment of women and minorities should
be presented. Efforts to enlist minority institutions in the
study must be documented.
o Inclusion of Children
It is the policy of NIH that children (i.e. individuals under
the age of 21) must be included in all human subjects research,
conducted or supported by the NIH, unless there are scientific
and ethical reasons not to include them. This policy applies
to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998. All investigators proposing research
involving human subjects should read the "NIH Policy and Guidelines
on the Inclusion of Children as Participants in Research Involving
Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
A SEPARATE section of the application should include the
following: The literature and/or data sets must be reviewed
to indicate to the extent possible (a) the distribution, by
appropriate age groupings, of the US population with the disease
or health problem under investigation and (b) whether the
impact of the intervention may be expected to vary according
to age. Specific goals for the recruitment of children and
plans for achieving these goals must be explicitly stated.
Approximate percentages of children, in appropriate age or
Initiated Clinical Trials Guidelines categories, expected
in the study sample and the basis for these estimates must
be provided. Generally, representation of children will not
be considered adequate unless they occur in the study population
in the same proportions as in the U.S. population having the
disease entity being studied Outreach and/or sampling plans
to ensure adequate representation of children must be presented.
Past track records in recruitment of children should be presented.
o Reporting Format
In addition to the written plans for the inclusion of women,
minorities, and children in the proposed clinical study, the
composition MUST be provided using the "Targeted/Planned
Enrollment Format Page" and/or "Enrollment Format Page"
as applicable, from the PHS 398 (rev.5/01).
o Study Organization and Administration
Describe the organization of the study and how the trial
will be managed. Include a description of the role of any
internal or external advisory committees, including the data
and safety monitoring committee, the responsibility and authority
of the director of the data coordinating center, and policies
and methods concerning blinding of study results. Discuss
the coordination of any centers or cores proposed. Include
a complete description of any sub-contracts for personnel
or facilities. Documentation of commitment, co-signed by a
business official and the principal investigator at the participating
center, must be included with the application. A timetable
for completion of the various stages of the trial should also
be included.
o Investigators
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. Such experience must be
carefully documented. Biographical sketches for all key investigators
must be provided. Most clinical trial designs will require
a multidisciplinary team.
Each center or core proposed must have a director designated.
The experience of each director must be carefully documented.
In addition, the authority of each center or core director
within the study must be specified.
o Other Support
"Other Support" pages must be provided for all key personnel.
Key personnel are individuals who contribute in a substantive
way to either the scientific development or execution of the
project. Key personnel will often include non-doctorate level
individuals, such as nurse coordinators. Time spent on each
project should be reported, regardless of whether remuneration
is received for that time/effort. ALL funding in support of
research endeavors should be reported. If the total effort
of active and pending grants during the study period exceeds
100 percent for any key personnel, indicate clearly what adjustments
will be made to which studies; general or "boilerplate" statements
concerning reductions in effort are not acceptable. Incomplete
or inadequate Other Support statements may result in delays
in review.
o Facilities
Clinical, data management, and laboratory facilities and
required equipment should be described in detail for all participating
institutions.
o Budget
A total overall budget and a complete, justified budget for
each year of support must be prepared. If the trial is designed
for more than a five year period, complete, justified budgets
for the future years also must be included. If the study involves
multiple centers, an additional composite budget matrix must
be prepared showing the costs for each center. Separate and
complete budgets must be prepared for each center. If part
of the costs of the trial are 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 commit the institution. Further information
concerning budget preparation can be obtained from the Chief
of the Grants Operations Branch.
D. DATA AND SAFETY MONITORING
As of the October 2000 receipt date (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html)
applicants must supply a general description of the Data and
Safety Monitoring Plan for all clinical trials as part of
the research application. A SEPARATE section of the application
should include a general description of the plan, and describe
the entity that will be responsible for monitoring, and the
policy and procedures for adverse event reporting. All monitoring
plans must include a description of how Adverse Events will
be reported to the Institutional Review Board (IRB), the NIH,
the Office of Biotechnology Activities (if required), and
the Food and Drug Administration in accordance with IND or
IDE regulations.
NIH requires the establishment of Data and Safety Monitoring
Boards (DSMBs) for 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. 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. Potential members of this board should NOT be
named in the application.
E. 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 an assistance mode. If such
Involvement is deemed appropriate by the Institute, the award
mechanism will be a cooperative agreement. Regardless of the
mechanism of support, the NHLBI staff will closely monitor
progress during the award. This monitoring may include 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 centers at specific
time periods, accrual goals for women and minorities (as appropriate),
any requirements regarding minimum effort of specific investigators,
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.
F. 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.
G. NHLBI REVIEW OF APPLICATIONS
In the initial peer review by NHLBI, multicenter applications
are reviewed by the Clinical Trials Review Committee or, if
necessary, by a Special Emphasis Panel. The usual review is
based on the application without contacting the investigators.
In rare cases, applicants may be contacted by telephone. This
initial peer review is concerned with scientific, technical,
and management issues (see below).
For the initial review of the OVERALL CLINICAL TRIAL application,
the review criteria will include:
o The importance of the question(s) and the need for and
significance of the trial, i.e., its potential impact. Costs
and benefits of the study also will be considered.
o The technical and scientific merit of the clinical aspects
of the study.
o The overall feasibility and likelihood of achieving the
trial goals, and the potential for a successful trial.
o Any pilot phase experience, including evidence of patient
accession and retention and the functioning of any laboratories
and coordinating center.
o Adequacy of the statistical features of the study, including
sample size projections and statistical power estimates, analytic
methods, and use of sequential analyses of data where indicated.
o The logistical aspects of the project including the accumulation,
flow, and quality control of data, proper randomization and
masking procedures, the operation of any central laboratories,
and plans for defining access to the data.
o The availability of participants suitable for the trial
(including women, children, and minorities), the likelihood
of their participation, and the likelihood of their remaining
in the study until the completion of followup.
o Reasonableness of the recruitment schedule.
o The qualifications, experience, and availability of key
investigators in the content area of the trial and in the
conduct of clinical trials in general.
o The adequacy of ethical and human safety issues, including
current institutional human subjects review board approval(s)
and forms for informed consent.
o An adequately documented working plan for the trial.
o The likelihood of successfully administering a cohesive
collaborative effort, where appropriate.
o The appropriateness of the budget.
For the initial review of individual FIELD CENTERS, the criteria
will include:
o The commitment of the institution and staff to a collaborative
protocol and to the success of the study. Letters of agreement
from collaborating investigators countersigned by appropriate
university officials must be included with the application.
o The availability of subjects suitable for the trial and
the likelihood of their participation, including adequacy
of the outreach or sampling plan to assure adequate female
and minority participation.
o The adequacy of ethical and human safety issues and issues
of the biohazard safety of employees (if applicable).
o The qualifications, experience, and availability of key
investigators.
o The adequacy of the facilities, including technical resources
and space.
o The appropriateness of the local organization and administration.
o The appropriateness of the budget.
For the initial review of a COORDINATING CENTER, the criteria
will include:
o The adequacy of plans for monitoring the collection, management,
and statistical analysis of the data, including periodic checks
of the data and reports to staff and the data and safety monitoring
board.
o The involvement of coordinating center staff in the overall
study design, including protocol development, and data collection,
coding, quality control, and data management.
o The qualifications, experience, and availability of key
investigators. The responsibility and authority of the Director
of the Coordinating Center must be clearly specified.
o The adequacy of the mechanisms proposed to provide advice
concerning overall policy, publications, and data and safety
monitoring.
o The adequacy of the organizational and administrative structure
of the proposed center.
o The adequacy and availability of the facility, including
technical resources and space.
o The appropriateness of the budget.
For the initial review of any ADMINISTRATIVE CENTERS OR CORE
FACILITIES analogous criteria will be used, appropriate to
the tasks of the laboratories.
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.
H. SUBMISSION OF APPLICATION
Receipt dates for all Investigator-Initiated Clinical Trial
grant applications are as follows:
Receipt Review by Clinical
Review by NHLBI Earliest
Date Trials Review Comm.
National Advisory Award
or SEP
Council
Date
Feb. 1 June/July
October
Dec. 1
June 1 October/November
February
April 1
Oct. 1 February/March
May
July 1
NOTE THAT THERE IS ONLY ONE RECEIPT DATE PER ROUND FOR
NHLBI REVIEWED APPLICATIONS REGARDLESS OF WHETHER THEY
ARE NEW, RENEWAL, OR AMENDED.
Failure to meet this deadline may result in delay of a round
in review of the application.
The National Institutes of Health's Division of Research
Grants has the responsibility for assigning applications to
the appropriate Institute. An assignment to NHLBI will be
based on the goals of the proposed program.
The original and FOUR copies of the completed application
must be mailed to the Center for Scientific Review; address
labels are included in PHS Form 398 kits.
In addition to the copies submitted to the Center for Scientific
Review, two courtesy copies should be sent, under separate
cover, to:
Scientific Review Administrator
Clinical Trials Review Committee
National Heart, Lung, and Blood Institute
Room 7194, Rockledge 2 Building
6701 Rockledge Drive
Bethesda, Maryland, 20892-7924.
Submission of separate copies to NHLBI will allow more time
for the Scientific Review Administrator to study the application
and plan for its review.
I. CONTACTS FOR FURTHER INFORMATION
Director, Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 10160
Bethesda, Maryland 20892-7950
(301-435-0080)
Director, Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 9160
Bethesda, Maryland 20892-7940
(301-435-0466)
Director, Division of Lung Diseases
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 10018
Bethesda, Maryland 20892-7952
(301-435-0233)
Director, Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 8100
Bethesda, Maryland 20892-7938
(301-435-0422)
Scientific Review Administrator
Clinical Trials Review Committee
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 7194
Bethesda, Maryland 20892-7924
(301-435-0288)
Chief, Grants Operations Branch
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 7154
Bethesda, Maryland 20892-7926
(301-435-0166)
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