RESEARCH ON CRYSTAL DEPOSITION ARTHROPATHIES
 
RELEASE DATE:  December 5, 2003
 
RFA Number:  RFA-AR-04-006

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)
 
COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
 (http://www.nih.gov/niams/)
National Institute on Aging (NIA)
 (http://www.nih.gov/nia/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER:  93.846 (NIAMS) and 93.866 (NIA)
 
LETTER OF INTENT RECEIPT DATE:  July 19, 2004
APPLICATION RECEIPT DATE:  August 19, 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 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 Arthritis and Musculoskeletal and Skin 
Diseases (NIAMS) and the National Institute on Aging (NIA) invite 
applications for research on improved diagnosis and treatment of the 
major crystal deposition arthropathies including gout, calcium 
pyrophosphate dihydrate (CPPD) crystal deposition disease and 
hydroxyapatite crystal deposition disease (also known as basic calcium 
phosphate crystallopathy).  The applications may be for individual 
research projects (R01) or for exploratory/developmental grants (R21).  
The crystal deposition arthropathies constitute significant public 
health problems.  These problems are anticipated to grow in scope in 
view of the increased number of elderly in our population, and the 
increasing numbers of people with osteoarthritis predisposing cartilage 
to calcification disorders.  The Request for Applications (RFA) is 
based, in part, on the scientific opportunities identified in the NIAMS 
Roundtable held in 2003: "Opportunities for Translational Research on 
Articular Crystal Deposition Diseases:  Gout, CPPD Crystal Deposition 
Disease, Hydroxyapatite Deposition Arthropathy."

RESEARCH OBJECTIVES

Gout is caused by the deposition of uric acid (monosodium urate) 
crystals in connective tissue and in the joint space.  Clinical 
manifestations include bouts of gouty arthritis, tophaceous deposits, 
uric acid and calcium oxalate kidney stones, and, rarely, interstitial 
nephropathy.  In some cases, uric acid crystals in the joints trigger 
severe destruction of articular cartilage, leading to pain and 
disability.

Uric acid is the normal end product of purine metabolism in humans.  It 
is generated as a result of nucleotide turnover and breakdown of 
dietary purines, and its elimination is controlled primarily by the 
kidneys.  Because the human uric acid oxidase (uricase) gene contains a 
mutation that renders it transcriptionally silent, normal serum levels 
of uric acid are very close to the level at which urate becomes 
insoluble in vitro, rendering urate balance precarious.  Although 
elevated serum uric acid levels are the first sign of gout, only about 
20% of people with hyperuricemia develop the disease.

Gout affects approximately 1% of the U.S. population, and remains a 
significant public health concern.  The prevalence of gout is much 
higher in certain ethnic groups, including Asian Pacific Islanders, 
Filipinos, Maoris, and Samoans.  Gout prevalence is also reportedly 
rising in African Americans.  Although gout primarily affects men, 
disease prevalence is increasing among elderly women along with 
increased longevity, and may be linked to the common use of diuretics 
and chronic renal insufficiency in this population.  Reduced estrogen 
levels in postmenopausal women may also play a role, as estrogen is a 
uricosuric agent.

Refractory gout still exists, and the numbers of affected patients may, 
in fact, be increasing.  This could be due to the limited scope of 
currently available urate-lowering drugs and the relatively common and 
potentially life-threatening toxicity of the most versatile uric acid–
lowering drug, allopurinol, which blocks urate production by inhibiting 
xanthine oxidase.  Another contributing factor is the increasing number 
of people receiving kidney and heart transplants and the use of 
cyclosporine to prevent tissue rejection in these patients.  More than 
10% of transplant patients develop gout within 3 years of treatment 
with cyclosporine, and the rapidly expanding tophi and severe attacks 
of gouty arthritis that occur in these patients are often refractory to 
therapy.

The development of new treatments for gout has not kept pace with 
medical needs.  An estimated 10–20% of gout cases in the U.S. are 
refractory to treatment because patients either cannot take allopurinol 
or are resistant to the drug.  In addition, the effectiveness of 
uricosuric drugs such as probenecid is limited by various factors.  The 
principal therapies for acute gout attacks, i.e., nonsteroidal anti-
inflammatory drugs (including COX-2 inhibitors), glucocorticoids, and 
colchicine, also have limitations and cannot prevent the progressive 
crystal-induced connective tissue destruction that occurs in some gout 
patients.

Non-urate calcium-containing crystal deposition diseases that affect 
the joints and surrounding structures include calcium pyrophosphate 
dihydrate (CPPD) crystal deposition disease and hydroxyapatite crystal 
deposition disease (also known as basic calcium phosphate 
crystallopathy).  Some individuals have a mixture of CPPD and 
hydroxyapatite crystals in affected joints.  The prevalence and 
incidence of calcium crystal arthropathies are expected to increase as 
a result of the growing elderly population in the U.S. and increasing 
numbers of people with osteoarthritis predisposing cartilage to 
calcification disorders.

Manifestations of CPPD disease may include intermittent attacks of 
pseudogout (acute inflammatory arthritis), chronic degenerative 
arthropathy, and calcification of articular cartilage.  CPPD disease 
can occur idiopathically, and in rare cases as a hereditary condition.  
Crystal deposition may be associated with a variety of metabolic 
disorders and can also occur as a result of trauma, injury or surgery.

The basic calcium phosphate arthropathies include calcific 
periarthritis syndromes that can occur as primary or secondary disease 
manifestations and may occur in a familial fashion, in calcific 
tendonitis and bursitis, intraarticular arthropathies such as Milwaukee 
shoulder syndrome, and periarthropathies.  Tumoral calcinosis syndrome 
is a rare form of basic calcium phosphate marked by large, 
periarticular tophaceous deposits containing hydroxyapatite and other 
basic calcium phosphate crystals.

CPPD or hydroxyapatite crystals are present in synovial fluid extracted 
from the joints of 30-60% of people with osteoarthritis, however, a 
distinct pattern of joint involvement distinguishes CPPD and 
hydryoxyapatite deposition diseases from "garden variety" 
osteoarthritis.  Definitive diagnosis of the calcium crystal deposition 
arthropathies is made by identifying specific crystal types in synovial 
fluid samples, which can be technically difficult.  Chondrocalcinosis 
and other soft tissue calcification may also be visible on X rays of 
joints in some patients, although these patients may be asymptomatic.

CPPD and hydroxyapatite crystals may also contribute directly or 
indirectly to osteoarthritis (OA).  However, the mechanisms involved 
are still unclear, and there is controversy as to whether crystals can 
actually cause OA in some cases rather than just exacerbating the 
disease.

In addition to studies of possible direct and indirect effects of 
crystals on OA, ongoing research on calcium crystal arthropathies 
includes studies of factors involved in cartilage mineralization, 
investigations using animal models of articular calcification, and 
genetic studies of familial disorders of calcium crystal deposition.  
Recent advances include the identification of two molecules that play a 
key role in some forms of CPPD and hydroxyapatite deposition diseases: 
the pyrophosphate-generating ectoenzyme PC-1 (a nucleoside triphosphate 
pyrophosphohydrolase) and ANKH, a multiple-pass transmembrane protein 
expressed in articular cartilage and other tissues that is a putative 
pyrophosphate transporter.  Inorganic pyrophosphate is both a potent 
inhibitor of hydroxyapatite deposition and an essential component of 
CPPD crystals, indicating that it plays a central role in calcium 
crystal deposition diseases.

This RFA is intended to stimulate research aimed at elucidating the 
pathogenesis of these disorders and engender the development of 
improved methods of diagnosis and treatment.  Topics of interest 
include but are not limited to:

Gout:

o Improving understanding of the fundamental pathobiology of gout, 
including formation of tophi and the relationship between crystals and 
pathology in arthritis
o Addressing the problem of treatment failure
o Determining why uric acid crystal deposition occurs in only some 
people with hyperuricemia, with the goal of developing approaches that 
prevent crystal formation in susceptible individuals
o Developing new methods for early diagnosis
o Conducting small-scale epidemiologic studies on gout
o Studying the genetic basis of drug responsiveness and drug resistance
o Developing new therapeutic agents
o Developing new animal models

Calcium Crystal Arthropathies:

o Improving understanding of the relationship between calcium crystals 
and pathology
o Improving understanding of the basic biology of the link between 
aging tissue changes and development of calcium crystal deposition 
diseases
o Clarifying the relationship between calcium crystal deposition and 
osteoarthritis
o Determining why some people with OA develop CPPD crystals in their 
joints, some develop hydroxyapatite crystals, and some develop both
o Developing methods for early diagnosis of disease using biomarkers 
and imaging modalities
o Identifying of  risk factors for disease 
o Developing new treatments, including ways to alleviate problems in 
patients who already have crystal deposits as well as ways to prevent 
crystal formation in specific joints, such as the knee, hip, shoulder, 
temporomandibular joint, etc.
o Developing new animal models

Please note that large-scale clinical and epidemiologic studies are 
beyond the scope of this RFA.

MECHANISMS OF SUPPORT
 
This RFA will use the NIH R01 (investigator-initiated research project 
grant) and the R21 (exploratory/developmental research grant) award 
mechanisms.  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 June 1, 2005.   
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.

R01 Applications.  Because the nature and scope of the research 
proposed in response to this RFA may vary, it is anticipated that the 
size of an award will vary also.  This RFA uses just-in-time concepts.  
It also uses the modular as well as the non-modular budgeting formats 
(see http://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 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.

R21 Applications.  This mechanism is to be used by investigators 
experienced in arthritis and musculoskeletal diseases research who wish 
to conduct innovative, high-risk studies.  Also encouraged to apply are 
investigators with expertise in fields other than arthritis and 
musculoskeletal diseases that wish to establish new research programs 
on these diseases.

Exploratory/developmental studies are not intended for large-scale 
undertakings or to support or supplement ongoing research.  Instead, 
investigators are encouraged to explore the feasibility of an 
innovative research question or approach which may not be justifiable 
through existing research to compete as a standard research project 
grant (e.g., R01), and to develop a research basis for a subsequent 
application through other mechanisms, i.e., R01, P01.

Exploratory/developmental (R21) grants may not exceed $100,000 per year 
in direct costs.  The total project period for an R21 application 
submitted in response to this RFA may not exceed two years.  These 
grants are non-renewable and continuation of projects developed under 
the R21 program will be through the traditional unsolicited (R01 or 
P01) grant programs.

This RFA uses just-in-time concepts.  It also used the modular 
budgeting as well as the non-modular budgeting formats (see  
http://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 budget format.  
Otherwise follow the instructions for non-modular budget research grant 
applications.  This program does not require cost sharing as defined in 
the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps2001/part_i_1.htm.

Investigators proposing to conduct small, pilot/toxicity clinical 
trials are advised to review the NIAMS guidelines for preparation of 
clinical trial applications and the NIAMS guidelines for Data and 
Safety Monitoring Boards (http://www.nih.gov/niams.htm).

FUNDS AVAILABLE 
 
The estimated funds available for the first year of support for the 
program are $1,200,000 in FY 2005 to fund 3 to 5 new grants in response 
to this RFA.  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 NIAMS 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. At this time, it is 
not known if this RFA will be reissued.
 
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:

Bernadette Tyree, Ph.D.
Director, Cartilage and Connective Tissue Program
NIAMS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD 20892-4872
Telephone:  (301) 594-5032
FAX:  (301) 480-1284
Email:  tyreeb@mail.nih.gov

Jill L. Carrington, Ph.D.
Director, Musculoskeletal Biology
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231
Bethesda, MD   20892
Telephone:   (301) 496-6402
FAX:   (301) 402-0010
Email:  Carringtonj@nia.nih.gov

o Direct your questions about peer review issues to:

Teresa Nesbitt, D.V.M., Ph.D.
Chief, Review Branch
NIAMS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD 20892-4872
Telephone:  (301) 594-4953
FAX:  (301) 480-4543
Email:  nesbittt@mail.nih.gov

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

Michael Morse
Grants Management Branch
NIAMS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD 20892-4872
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  morsem@mail.nih.gov

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD   20892
Telephone:  (301) 496-1472
FAX:  (301) 402-1758
Email:  whippl@nih.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 NIAMS 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:

Teresa Nesbitt, D.V.M., Ph.D.
Chief, Review Branch
NIAMS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD 20892-4872
Telephone:  (301) 594-4953
FAX:  (301) 480-4543
Email:  nesbittt@mail.nih.gov

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 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.

SUPPLEMENTARY INSTRUCTIONS

RESEARCH PLAN – The research plan (a-d) is limited to 25 pages for R01 
applications and 10 pages for R21 applications.  Applications that 
exceed the page limit will be returned without review.  An appendix may 
be included in the application; however, the appendix is not to be used 
to circumvent the page limit of the research plan.

For the R21 application, preliminary data supporting feasibility of 
approach are not required, however, if included, the section may not 
exceed 1 page.  In addition, a paragraph should be included in the 
Significance section of the application that specifies either how the 
project presents a new direction for the work performed in the PI's 
laboratory or the innovative nature of the research question or 
approach, and how it may advance understanding of the crystal 
deposition arthropathies.
 
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 
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.

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/labels.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:

Teresa Nesbitt, D.V.M., Ph.D.
Chief, Review Branch
NIAMS
One Democracy Plaza
6701 Democracy Boulevard, Suite 800, MSC 4872
Bethesda, MD 20892-4872
Telephone:  (301) 594-4953
FAX:  (301) 480-4543
Email:  nesbittt@mail.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 from the previous unfounded 
version of the application.

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

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 NIAMS 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 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 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, weighting 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, all R21 
applications will also be reviewed with respect to the following:

o In the context of this RFA, the R21 exploratory/developmental grants 
are to be used to either: a) gather preliminary data to develop a 
research basis for a subsequent application through other mechanisms, 
i.e., R01, P01 or b) explore the feasibility of an innovative or 
conceptually creative research question or approach that may not be 
justifiable through existing research to compete as a standard research 
project grant (e.g., R01).

o Preliminary data supporting feasibility of approach are not required.

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.  

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:  July 19, 2004
Application Receipt Date:  August 19, 2004
Peer Review Date:  TBA
Council Review:  May, 2005
Earliest Anticipated Start Date:  June 1, 2005

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 studies (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 potential risk to 
the participants.   (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 RFA 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 and92. 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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