THE ETIOLOGY, PATHOGENESIS AND TREATMENT OF ALS

RELEASE DATE:  August 8, 2003

RFA Number:  RFA-NS-04-003

Department of Veteran's Affairs (VA)
 (http://www.va.gov/resdev/)
National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov/)
The Amyotrophic Lateral Sclerosis Association (ALSA)
 (http://www.alsa.org)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.853 (NINDS)

LETTER OF INTENT RECEIPT DATE:  September 30, 2003

APPLICATION RECEIPT DATE:  October 22, 2003

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 Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

With this Announcement, the Department of Veterans Affairs (VA), the 
National Institute of Neurological Disorders and Stroke (NINDS) and the 
Amyotrophic Lateral Sclerosis Association (ALSA) invite research grant 
applications that address the etiology, pathogenesis and treatment of 
Amyotrophic Lateral Sclerosis.

RESEARCH OBJECTIVES

Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which 
those motor neurons that control voluntary movement are progressively 
lost while those that subserve other functions such as cognition and 
sensation are spared.  At this time victims have no effective treatment 
options; 50% die within three years of symptom onset and 80-90% within 
five years.

ALS most likely represents a syndrome of very closely related disorders 
resulting from numerous causes.  Although degeneration may start in 
either lower (spinal) or upper (cortico-spinal) motor neurons, both 
populations of neurons eventually become involved. Cytologically, 
neurons exhibit loss of dendrites, derangement of the cytoskeleton and 
accumulation of a variety of proteins, some of which may form inclusion 
bodies.  Muscular atrophy occurs secondary to denervation; some degree 
of peripheral reinnervation has been observed relatively early in the 
course of the disease but the extent is markedly less than that observed 
in other motor neuropathies.  The disease is strikingly specific for 
motor neurons; indeed one of the many tragedies of ALS is that patients 
suffer with their sensory, cognitive, and emotional faculties 
essentially unaffected.

ALS has a complex and incompletely understood etiology.  Approximately 5 
- 10% of cases have another affected family member (fALS) but in the 
majority of cases the underlying cause and primary pathogenic mechanism 
remain unknown.  While each series of cases has a distinct presentation, 
there is reason to believe that all cases can provide information 
concerning common or convergent pathogenic mechanisms relevant to 
sporadic ALS (sALS).  Furthermore, new analytic methodologies can 
identify genetic factors that affect traits other than risk that may be 
important in sporadic ALS (e.g. rate of progression, site of onset).

Notwithstanding the opportunities presented by the study of genetic 
forms of the disease, it is clear that ALS is in most cases a 
multifactorial disorder triggered by as yet unknown factors, including 
exposure to toxicants in the environment (either alone or in combination 
with specific genetic factors).  Incidence and prevalence are observed 
to be generally uniform worldwide.  While specific toxicants have been 
studied for decades in an isolated, at-risk population in the Western 
Pacific, recent reports have identified an approximately two-fold 
increase in the risk of developing ALS among military personnel deployed 
to SW Asia during the period of the Gulf War (Aug '90 to Jul '91) 
relative to non-deployed personnel.

Four broad classes of pathogenic mechanisms are hypothesized to produce 
the cellular dysfunction and death that produce the clinical syndrome of 
ALS: 1) mitochondrial dysfunction/oxidative stress; 2) altered/disrupted 
protein processing; 3) excitotoxicity/altered calcium homeostasis; and 
4) altered cytoskeletal function/axonal transport.  While these 
hypotheses focus on motor neurons as the final common pathway of the 
expression of ALS, there is increasing recognition of the contributions 
of non-neuronal cells to the pathogenesis of ALS. These may represent 
novel opportunities to develop therapeutic strategies to address more 
"upstream" events in the primary pathophysiologic cascade or to 
ameliorate the effects of secondary pathogenic processes.

At present there is no effective treatment for ALS.  However, because 
spinal motor neurons extend beyond the blood brain barrier, they may be 
accessible to therapies that are not feasible for other neurons in the 
CNS.  Alternatively, recent advances in neurobiology may allow the 
development of strategies to promote re-innervation of muscle.  
Regardless, the development of novel strategies and technologies for the 
development and delivery of therapeutics remains an important goal in 
ALS research.

In summary, there remain important gaps in our understanding of the 
continuum of pathogenesis, pathophysiology, treatment and prevention of 
ALS.  Accordingly, the NINDS, VA and ALSA have formed a public/private 
partnership to solicit applications to support research in three general 
lines of investigation: causative factors, pathobiology of motor neurons 
and associated cell types and the diagnosis and treatment of ALS.  
Specific topics include, but are not limited to:

o Epidemiology – Sporadic ALS constitutes the great majority of typical 
ALS but we do not have an adequate understanding of non-genetic risk 
factors.  Identifying specific genetic and environmental causes 
typically requires large-scale, long-term, incidence-based studies that 
are not feasible with the resources available in this initiative.  
However, several strategies of lesser scope may be feasible including: 
studies that focus on candidate toxicants (glutamate and glutamate 
analogues, those relevant to the neuromuscular system, mitochondrial 
inhibitors, etc.), studies that focus on populations at elevated risk, 
data mining of existing databases or the development of epidemiologic 
resources such as a national case control series.

o Genetic Factors – Studies that focus on the interactions of genes with 
other genes and/or environmental factors are of particular interest.  
Appropriate topics include studies of genetic background effects (i.e., 
strain surveys, crosses with important other genetically modified mice, 
etc.), environmental interactions (non-mammalian systems present 
opportunities to study topics such as infectious agents as triggers and 
putative environmental toxicants), and the biologic basis of age-
dependent motor neuron vulnerability. Classic gene discovery efforts are 
supported by complementary, ongoing efforts and will not be considered 
responsive to this RFA.

o Cell / Cell Interactions – Despite the increasing awareness that ALS 
is not a disorder of cell autonomous death, our understanding of the 
signaling between the cell types involved or even the certain 
identification of the cell types involved is relatively rudimentary.  
Other important considerations include the switch from protective to 
pathogenic contributions, the interaction between neuronal oxidative 
stress and cytokines elaborated by non-neuronal cells.  Mice with genes 
expressed (or deleted) in a cell-specific manner may be particularly 
informative in this regard.

o Cellular and Organellar Dysfunction – Notwithstanding contributions 
from other cell types, ALS is ultimately the expression of motor neuron 
death and dysfunction resulting from incompletely understood mechanisms 
(including upstream activators, non-apoptotic contributions of 
mitochondrial pathology, endoplasmic reticulum stress, etc).  There is 
also a re-emerging appreciation of the axon as an early pathological 
target in ALS.  Recent advances in our understanding of axonal transport 
and axonal responsiveness to trophic factors may provide new 
opportunities to investigate pathogenesis in order to develop therapies 
and restorative strategies.

o Protein and Molecular Dysfunction – As discussed above, four general 
classes of pathogenic processes have been observed in patients and 
animal models.  A better understanding of the contribution of each of 
these processes to the course of the disease may provide opportunities 
to alter the course of ALS.  Other, new opportunities also include 
alterations in metal handling (Zn2+, effects of metallothionein 
knockouts), altered axonal transport and the question of whether 
aggregates are pathogenic or protective.

o Novel Approaches to Delivery of Therapeutic Agents – Spinal motor 
neurons may be uniquely unconstrained by the blood-brain barrier, 
nonetheless delivery of therapeutics remains a challenge and new 
approaches are clearly indicated.  These may entail strategies directly 
targeting the neuron (specifically/receptor mediated or non-
specifically/endocytic) or by exploiting motor neurons' close functional 
relationship with other cell types (e.g. muscle as a reservoir).

o Biomarkers - Biomarkers are critical for early disease detection and 
more efficient clinical trials. Genomic, proteomic, metabolomic and 
other novel techniques may be very powerful in the search for 
biomarkers.

MECHANISM OF SUPPORT

This public/private partnership involves the research programs of the 
VA, NINDS and the ALSA.  Applications are solicited from VA-based 
research laboratories, academic-based laboratories and other research 
enterprises.  The RFA will use both VA and NIH award mechanisms: VA 
Merit Review Awards http://www.va.gov/resdev/directive/mrs.cfm ($500,000 
direct cost over two years, no indirect costs) for VA-eligible research 
laboratories and NIH R21 Awards ($275,000 direct cost over two years, 
standard NIH indirect costs) for academic-based and other research 
laboratories. 
(See http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html)

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 at VA and the NIH.  The anticipated award date is March 2004.  
Applications that are not funded in the competition described in this 
RFA may be resubmitted as NEW investigator-initiated applications at 
either the VA or NIH using the standard guidelines and receipt dates for 
NEW applications.   

This RFA uses just-in-time concepts.  It also uses the modular budgeting 
format for R21 awards. (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an R21 application, use the modular 
format.  This program does not require cost sharing as defined in the 
current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.  

FUNDS AVAILABLE

Together, the participating organizations intend to commit a total of 
approximately $2.4 million in FY 04 to fund approximately 10 new grants 
in response to this RFA.  An applicant may request a project period of 
up to 2 years and a budget for direct costs of up to $275,000 over the 
course of two years for NIH awards or a budget for direct costs of up to 
$500,000 over the course of two years for VA awards.  This RFA is 
considered to be a VA special initiative and is open to all eligible VA 
investigators, regardless of their current VA funding.  VA-eligible 
investigators selected for non-VA funding will be allowed to resubmit 
their budget to meet the NIH budgetary restrictions above (see "SPECIFIC 
INSTRUCTIONS FOR VA GRANT APPLICATIONS").  Although the financial plans 
of the participating institutions 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
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.  

Individuals wishing to apply for VA funding must meet all VA eligibility 
criteria.  VA Central Office will verify the eligibility of all 
investigators applying for VA funding prior to review.

SPECIAL REQUIREMENTS

The sponsoring organizations have issued several solicitations in areas 
with significant intellectual or technical overlap with the current 
proposals.  In order to preserve the focus of each initiative, 
applications will not be considered responsive to this RFA if their 
principal focus is:
o Translational Studies including high throughput drug screens in 
disease models i.e. applications responsive to PAR-02-139 (NINDS 
Cooperative Program in Translational Research), PAR-02-138 (NINDS 
Exploratory/Developmental Projects in Translational Research) or 
NOT-NS-03-003 (NINDS Administrative Supplements: Testing of Candidate Drug 
Treatments for Neurodegeneration in Rodent Models)
o Gene Discovery in human populations, i.e. applications responsive to 
PAS-03-092 (Gene Discovery for Complex Neurological and Neurobehavioral 
Disorders)
o DNA Repositories or Patient registries, i.e. applications responsive 
to NOT-NS-02-012 (Human Genetic Resource Center: DNA and Cell Line 
Repository) or NOT-NS-02-002 (Genetic Resource Center)

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:

Paul A. Sheehy, Ph.D.
Neurodegeneration Cluster
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Rm. 2214A
Rockville, MD 20892-9525
(301) 496-5329 (v)
(301) 480-1080 (f)
sheehyp@ninds.nih.gov

William J. Goldberg, PhD
Medical Research Service (121E)
Department of Veteran's Affairs
1400I St., NW
Washington, DC 20005
(202) 408-3611 (v)
(202) 275-6100 (f)
william.goldberg@hq.med.va.gov

o Direct your questions about peer review issues to:

Alan Willard, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Rm. 3208
Rockville, MD 20892-9529 (for courier service)
(301) 496-9223 (v)
(301) 402- 0182 (f)
willarda@ninds.nih.gov

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

Michael Loewe
Grants Management Officer
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Rm. 3258
Rockville, MD 20892-9525
(301) 496-9231 (v)
(301) 402-4370 (f)
loewem@ninds.nih.gov

William J. Goldberg, PhD
Medical Research Service (121E)
Department of Veteran's Affairs
1400I St., NW
Washington, DC 20005
(202) 408-3611 (v)
(202) 275-6100 (f)
william.goldberg@hq.med.va.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:

Paul A. Sheehy, Ph.D.
Neurodegeneration Cluster
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Rm. 3208
Rockville, MD 20892-9525
(301) 496-5329 (v)
(301) 480-1080 (f)
sheehyp@ninds.nih.gov

SUBMITTING AN APPLICATION

All applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

SUPPLEMENTAL INSTRUCTIONS: The Research Plan section in applications for 
both NIH and VA awards may not exceed 15 pages.  No appendices are 
permitted.  Applications for NIH awards should use the modular budget 
format (see "SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS").  
Applications for VA awards will initially also use the NIH modular 
budget format (see "SPECIFIC INSTRUCTIONS FOR VA GRANT APPLICATIONS").

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: NIH applications 
requesting up to $275,000 direct cost over two years 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 http://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 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR VA GRANT APPLICATIONS: Investigators eligible 
to apply for VA funding ($500,000 direct cost over two years, no 
indirect costs) should indicate their VA Medical Center as the academic 
institution and obtain the appropriate signatures.  For the purpose of 
initial processing, the application submitted should include a modular 
budget of up to $250,000 per year for two years prepared according to 
the PHS 398 format (see above).  Those selected for funding will be 
required to revise and resubmit budgets prepared on VA Merit Review 
budget forms 10-1313-3 and 10-1313-4.

VA investigators who submit for VA funding may be selected for non-VA 
funding.  If so, they will be requested to submit a revised cover page 
indicating their academic institution and appropriate signatures.  VA 
investigators selected for non-VA funding will also be requested to 
revise and resubmit their budget to meet the NIH budgetary restrictions 
for this RFA ($275,000 direct cost over two years, in $25,000 modules, 
plus standard NIH indirect costs).  It is anticipated that such awards 
will be rare.

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: 
http://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 must 
be sent to:

Alan Willard, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Rm. 2214A
Rockville, MD 20892-9525 (for courier service)
(301) 496-9223 (v)
(301) 402- 0182 (f)
willarda@ninds.nih.gov

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.  While the investigator may 
still benefit from the previous review, the RFA application is not to 
state explicitly how.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the VA and the NINDS.  Incomplete applications 
will be returned to the applicant without further consideration.  And, 
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 NIH 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 sponsoring organizations in accordance with 
the review criteria stated below.  As part of the initial merit review, 
all applications will:

o Receive a written critique
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 second level review by an appropriate National Advisory 
Council or Board.
 
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 discuss the 
following aspects of the application in order to judge the likelihood 
that the proposed research will have a substantial impact on the pursuit 
of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The scientific review group will address and consider each of these 
criteria in assigning the application's overall score, weighting them as 
appropriate for each application.  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:

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 CONSIDERATIONS 

DATA SHARING:  The adequacy of the proposed plan to share data.

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:  September 30, 2003
Application Receipt Date:  October 22, 2003
Peer Review Date:  December 2003
Council Review:  February 2004
Earliest Anticipated Start Date:  March 1, 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 

MONITORING PLAN AND DATA AND SAFETY MONITORING BOARD: Research 
components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data and Safety Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

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 
(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.
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 
http://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 
http://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 http://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 
http://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 
http://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.health.gov/healthypeople.

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 
http://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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