HYPOGLYCEMIA IN PATIENTS WITH TYPE 1 DIABETES
 
RELEASE DATE:  August 14, 2003
 
RFA Number:  RFA-DK-03-017

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATIONS:

National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATIONS:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov)
National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)
 
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.847 and 93.853
 
LETTER OF INTENT RECEIPT DATE:  January 20, 2004

APPLICATION RECEIPT DATE:  February 20, 2004

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
and the National Institute of Neurological Disorders and Stroke (NINDS) invite 
applications for basic and clinical studies to enhance understanding and 
prevention of hypoglycemia in patients with diabetes. Large clinical trials 
have demonstrated the efficacy of intensified glucose control in the 
prevention of the long-term vascular complication of diabetes. However, 
episodes of severe hypoglycemia may complicate intensified treatment and are 
often a major obstacle to the achievement of euglycemia in many patients. This 
RFA seeks basic and clinical studies to 1) enhance understanding of how the 
brain and other critical tissues sense and respond to hypoglycemia, 2) 
delineate the effects of hypoglycemia on brain function and 3) develop 
improved methodologies to prevent hypoglycemia, based on an understanding of 
physiological glucose sensing and counterregulation.
 
RESEARCH OBJECTIVES

Background

The Diabetes Control and Complications Trial (DCCT), for type 1 diabetes, and 
the United Kingdom Prospective Diabetes Study (UKPDS), for type 2 diabetes, 
established the importance of intensified diabetes control in dramatically 
reducing the devastating complications that result from poorly controlled 
diabetes. However, with current treatment modalities, tight control remains 
an unattainable goal for many people with diabetes. For example, in the DCCT, 
fewer than 5% of individuals receiving intensified treatment maintained 
normal hemoglobin A1c levels.

To achieve glycemic control, many patients must walk a tightrope, balancing 
euglycemia against the danger of low blood glucose. Indeed, for many 
individuals with diabetes, episodes of severe hypoglycemia are the major 
obstacle to the achievement of euglycemia and the prevention of long-term 
complications. Hypoglycemia is frightening to patients and their families. In 
fact, for some individuals or their families, fear of hypoglycemia may 
outweigh concern over long-term complications of diabetes, leading to 
inadequate glycemic control. Fear of hypoglycemia is well-founded, as low 
blood glucose levels impart significant morbidity and mortality. Two to 4 per 
cent of deaths among individuals with type 1 diabetes have been attributed to 
hypoglycemia. Acutely, diminished brain function during a hypoglycemic 
episode poses potential physical danger to the patient. 

Recurrent hypoglycemia may impose long-lasting damaging effects on the brain, 
resulting in impairment of memory or other cognitive functions. This is 
especially a concern in the early childhood years when the nervous system is 
still developing. While there is substantial evidence that hypoglycemia 
alters human behavior, and recurrent episodes of severe hypoglycemia may lead 
to memory loss or impaired cognitive function, the pathogenesis of 
hypoglycemic-induced nerve cell injury is largely unknown.  Mechanisms that 
could result in damage to cells of the CNS include, but are not limited to, 
excitotoxicity related to a dysregulation of the glutamate-glutamine cycle or 
an impaired capacity of astrocytes to generate reducing equivalents in the 
presence of oxidative stress.  To understand the effects of acute or 
recurrent hypoglycemia on the cells of the central nervous system, it is 
essential to characterize the response of CNS cells to reduced glucose 
levels, to determine the extent of CNS cell injury induced by hypoglycemia, 
and to identify the mechanisms involved in hypogylcemia-induced cell or 
tissue damage in brain. 

In addition to adversely affecting cognition, recurrent hypoglycemia may also 
impair the body's defense mechanisms against hypoglycemia, creating a vicious 
cycle for the patient. Normally, hypoglycemia triggers a series of hormonal 
and neural responses designed to restore glucose concentration towards 
normal, to maintain brain metabolism. A component of this counterregulatory 
response is the secretion of epinephrine, which generates "neurogenic" 
symptoms (e.g., palpitations, sweating, anxiety) that serve to warn the 
patient of the dropping blood glucose. The patient can then take action 
(i.e., eat) to help reverse the hypoglycemia. A major problem in many 
individuals with diabetes is a progressive decay in the counterregulatory 
response over time, resulting in "hypoglycemia unawareness."  Epinephrine 
secretion is not triggered by falling blood glucose levels and, therefore, no 
neurogenic symptoms occur to warn the patient of a problem. The individual 
fails to become aware of hypoglycemia and does not initiate appropriate 
responses. This can result in prolonged hypoglycemia, with consequent brain 
injury, seizure or loss of consciousness. 

Catecholamines are not the only component of the counter-regulatory response.  
Since the description of leptin in 1995, there has been an explosion of new 
information concerning neuropeptides that are involved in regulating energy 
balance and how these neuropeptides interact with insulin. In addition, new 
physical and molecular imaging techniques have begun to allow more precise 
localization of the neural circuitry involved in glucose sensing. However, 
very little is known about the precise mechanisms that sense blood glucose 
and link that sensory machinery to the autonomic and endocrine responses 
which alert the patient to the low blood glucose, and, ultimately, restore 
glucose homeostasis. Research is needed to enhance understanding of the 
hypothalamic and peripheral control mechanisms that counteract hypoglycemia, 
and the pathogenic mechanisms involved in loss of counterregulatory control. 
In addition, research is needed to foster translation of new scientific 
discoveries into clinical approaches for reducing the occurrence of 
hypoglycemia and restoring counter-regulation.

Hypoglycemia occurs because of a mismatch between insulin dose, food intake 
and energy expenditure. Despite vigilant blood sugar monitoring and adherence 
to treatment regimens, euglycemia often cannot be achieved safely (i.e., 
without the occurrence of hypoglycemia), because current treatment modalities 
do not mimic normal, physiologically regulated insulin secretion. In 
addition, emerging evidence suggests that unrecognized, nocturnal 
hypoglycemia may contribute significantly to hypoglycemia unawareness and/or 
cognitive sequelae of hypoglycemia. 

Objectives and Scope

This RFA seeks basic and clinical studies to 1) enhance understanding of how 
the brain and other critical tissues sense and respond to hypoglycemia, 2) 
delineate the effects of hypoglycemia on brain function and 3) develop 
improved methodologies to prevent hypoglycemia, based on an understanding of 
physiological glucose sensing and counterregulation.

Recent scientific advances (e.g., the advent of new information regarding 
neurohumoral factors involved in energy metabolism, the development of new 
imaging technologies, and the availability of continuous glucose monitoring) 
potentially open up new avenues of exploration. Entry of neuroscientists and 
brain-imaging specialists into this field is highly encouraged, as are 
collaborative efforts between scientists in different disciplines (e.g., 
neuroscientist and diabetologist).

Appropriate topics for investigation under this RFA would include but are not 
limited to:

o   studies to understand the effect of diabetes and of hypoglycemia on the 
metabolism of glucose by the brain, including studies to identify transporters 
or signaling pathways that may be involved in the development or reaction to 
hypoglycemia, and studies to understand how changes in metabolism might 
contribute to hypoglycemia unawareness;

o   studies to understand the effect of hypoglycemia on brain neurochemistry, 
including studies that apply newly-developed sensors that measure 
neurotransmitters and substrates in the brain to diabetes;

o   studies of glucose-sensing mechanisms in the brain and peripheral tissues, 
including the development of neuronal cell lines that could be used for in 
vitro studies;

o   studies to investigate the role of sleep in the development of 
hypoglycemia and elucidate the molecular mechanisms involved in the promotion 
of hypoglycemia by sleep;

o   studies to explore the role of sleep on counterregulatory responses, and 
determine the role of nighttime hypoglycemia in loss of awareness;

o   studies to understand the mechanisms underlying defective 
counterregulation after recurrent hypoglycemia and the development of 
hypoglycemia unawareness;

o   studies to understand the mechanism of reversal of hypoglycemia 
unawareness by avoidance of hypoglycemia, including studies of patients after 
islet transplantation;

o   studies to carefully describe and understand the long-term effects of 
recurrent hypoglycemia on brain function. Such studies could involve animal 
models, as well as continuing clinical research over an extended period of 
time, including the use of advanced imaging technology. Of particular interest 
is the effect of hypoglycemia in very young children;

o   studies to assess the long-term adaptations of the CNS to recurrent 
episodes of hypoglycemia and the effects of hypoglycemia on synaptic 
plasticity;

o   application of existing imaging technologies, or the development of new 
methods to image brain function, especially in the hypothalamus, in order to 
understand the neurological and cognitive effects of hypoglycemia and the 
neural substrates of hypoglycemia unawareness.

MECHANISM OF SUPPORT
 
This RFA will use NIH Investigator-Initiated Research Project Grant (R01) and 
the Exploratory/Development Research Grant (R21) award mechanisms(s). As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  This RFA is a one-time solicitation.  Future 
unsolicited, competing-continuation applications based on this project will 
compete with all investigator-initiated applications and will be reviewed 
according to the customary peer review procedures. The anticipated award date 
is September 30, 2004.  Applications that are not funded in the competition 
described in this RFA may be resubmitted as NEW investigator-initiated 
applications using the standard receipt dates for NEW applications described 
in the instructions to the PHS 398 application. 

R21 (Exploratory/Developmental) grants

The R21 mechanism is intended to encourage new exploratory/developmental 
research projects by providing support for the early stages of their 
development.  Awards are made to demonstrate feasibility of a subsequent 
project and to obtain preliminary data testing innovative ideas.  Therefore, 
these grants are not renewable.  Continuation of projects developed under 
this program will be through the regular research project grant mechanism 
(for example, R01).  These grants are not intended to support or supplement 
ongoing funded research of an established investigator, or to serve as an 
alternative mechanism of support for projects not receiving funding as 
competitive continuation applications.  The NIH Grants Policy statement 
applies to these awards.

R01 (Research) grants

The R01 award represents an investigator-initiated research grant designed to 
support a discrete, specified research project performed by a principal 
investigator.  

This RFA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
https://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at 
https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.  

FUNDS AVAILABLE 
 
The participating IC(s) intends to commit approximately $3 million in FY04 to 
fund 6 to 12 new and/or competitive continuation grants in response to this 
RFA. An R01 applicant may request a project period of up to five years and a 
budget for direct costs of up to $450,000 per year. Applicants for the R21 
may request a project period of up to two years with a combined budget for 
direct costs of up to $275,000 for the two-year period. For example, the 
applicant may request $100,000 in the first year and $175,000 in the second 
year. The request should be tailored to meet the needs of the project. No 
more than $200,000 may be requested in a single year.

Further information about the R21 mechanism is available at:  
https://grants.nih.gov/grants/guide/pa-files/PA-03-107.html. Because the 
nature and scope of the proposed research will vary from application to 
application, it is anticipated that the size and duration of each award will 
also vary. Although the financial plans of the IC(s) provide support for this 
program, awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of meritorious applications.  
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics: 
   
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations 
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   
 
WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 
issues:

o Direct your questions about scientific/research issues to:

Barbara Linder, M.D., Ph.D. 
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 699
Bethesda, MD 20892-5460
Telephone:  (301) 594-0021
FAX:  (301) 480-3503
Email:  bl99n@nih.gov
 
Toby Behar, Ph.D.
Neural Environment Cluster                     
National Institute of Neurological Diseases  
Neuroscience Center,  Room 2114A  
6001 Executive Blvd.  
Bethesda, MD. 20892-9521  
Tel: (301) 496-1431  
Fax: (301) 480-2424  
Email:  tb72z@nih.gov

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email: fc15y@nih.gov

o Direct your questions about financial or grants management matters to:

Kathleen J. Shino, M.B.A.
Grants Management Branch
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 708 
Bethesda, MD  20892-5456
Telephone:  (301) 594-8869 
FAX:  (301) 480-3504
Email: ks48e@nih.gov

Karen Shields
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 3254
Bethesda, MD  20892
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: ks26n@nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows IC staff to estimate the potential review workload and plan 
the review.
 
The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:

Chief, Review Branch 
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752 
Bethesda, MD  20892-5452
(For express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a DUN and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com. The DUNS number should 
be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document 
is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, Telephone 
(301) 710-0267, Email: GrantsInfo@nih.gov.
 
SUPPLEMENTARY INSTRUCTIONS: Applications proposing studies involving patients 
who have received islet or pancreas transplants may not include 
transplantation costs in the budget.
  
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting 
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at 
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
https://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked. The RFA label is also available at: 
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and all 
copies of the appendix material must be sent to:

Chief, Review Branch 
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752 
Bethesda, MD  20892-5452
(For express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505

APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the applicant 
without review. 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes from the 
previous unfunded version of the application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the (IC). Incomplete applications will not be reviewed.

If the application is not responsive to the RFA, NIH staff may contact the 
applicant to determine whether to return the application to the applicant or 
submit it for review in competition with unsolicited applications at the next 
appropriate review cycle. 

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the National Diabetes and Digestive and Kidney Diseases in 
accordance with the review criteria stated below.  As part of the initial 
merit review, all applications will:

o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score
o Receive a written critique 
o Receive a second level review by an appropriate National Diabetes and 
Digestive and Kidney Disease Advisory Council. 
 
REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate the application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application's overall score, weighing them as appropriate for each 
application. 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The application does not need to be strong in all categories to be judged 
likely to have major scientific impact and thus deserve a high 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.

SIGNIFICANCE: Does this study address an important problem? If the aims of 
the application are achieved, how will scientific knowledge be advanced? What 
will be the effect of these studies on the concepts or methods that drive 
this field?

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project? Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

INNOVATION: Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?

INVESTIGATOR: Is the investigator appropriately trained and well suited to 
carry out this work? Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers (if any)?

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success? Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements? Is there evidence of institutional support?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

SPECIAL REVIEW CONSIDERATIONS FOR R21 APPLICATIONS: The NIH R21 
exploratory/developmental grant is a mechanism for supporting novel 
scientific ideas or new model systems, tools or technologies that have the 
potential to significantly advance our knowledge or the status of health-
related research.  Because the research plan is limited to 15 pages, an 
exploratory/developmental grant application need not have background material 
or preliminary information as one might normally expect in an R01 
application.  Accordingly, reviewers will focus their evaluation on the 
conceptual framework, the level of innovation, and the potential to 
significantly advance our knowledge or understanding.  Reviewers will place 
less emphasis on methodological details and certain indicators traditionally 
used in evaluating the scientific merit of R01 applications including 
supportive preliminary data.  Appropriate justification for the proposed work 
can be provided through literature citations, data from other sources, or, 
when available, from investigator-generated data.  Preliminary data are not 
required for R21 applications.

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, 
below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed. 

ADDITIONAL REVIEW CONSIDERATIONS:

SHARING REAEARCH DATA: Applicants requesting more than $500,000 in direct 
cost in any year of the proposed research must include a data sharing plan in 
their application.  The reasonableness of the data sharing plan or the 
rationale for not sharing research data will be assessed by the reviewers.  
However, reviewers will not factor the proposed data sharing plan into the 
determination of scientific merit or priority score. For additional 
information on sharing of research data see: 
https://grants.nih.gov/grants/policy/data_sharing.

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:          January 20, 2004
Application Receipt Date:               February 20, 2004
Peer Review Date:                       Summer 2004
Council Review:                         September 2004
Earliest Anticipated Start Date:        September 30, 2004

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm  

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy (phase II); efficacy, effectiveness, and 
comparative trials (phase III).  The establishment of data and safety 
monitoring boards (DSMBs) is required for multi-site clinical trials 
involving interventions that entail risks to participants (NIH Policy for 
Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html).

SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking more than $500,000 or 
more in direct costs in any single year are expected to include a plan for 
data sharing or state why this is not possible. 
https://grants.nih.gov/grants/policy/data_sharing  Investigators should seek 
guidance from their institutions, on issues related to institutional 
policies, local IRB rules, as well as local, state and Federal laws and 
regulations, including the Privacy Rule. Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the 
scientific merit or the priority score.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research. This policy results from the NIH Revitalization Act of 1993 (Section 
492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy 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 is available at 
https://grants.nih.gov/grants/funding/children/children.htm

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at http://stemcells.nih.gov/index.asp and at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA.  
It is important for applicants to understand the basic scope of this 
amendment.  NIH has provided guidance at 
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the "Standards for Privacy of Individually Identifiable Health Information", 
the "Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003 (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on "Am I a covered 
entity?"  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving 
the health promotion and disease prevention objectives of "Healthy People 
2010," a PHS-led national activity for setting priority areas. This RFA is 
related to one or more of the priority areas. Potential applicants may obtain 
a copy of "Healthy People 2010" at http://www.healthypeople.gov/ 

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
https://grants.nih.gov/grants/policy/policy.htm 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

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