CONSEQUENCES OF MARIJUANA USE ON THE DEVELOPING BRAIN

RELEASE DATE:  January 9, 2004

RFA Number:  RFA-DA-04-016

Department of Health and Human Services (DHHS)

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

COMPONENT OF PARTICIPATING ORGANIZATION: 
National Institute on Drug Abuse (NIDA) 
 (http://www.nida.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.279

LETTER OF INTENT RECEIPT DATE:  March 16, 2004
APPLICATION RECEIPT DATE:       April 16, 2004

THIS REQUEST FOR APPLICATIONS (RFA) CONTAINS THE FOLLOWING INFORMATION:

o Purpose of this RFA
o Research Objectives
o Mechanisms 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 purpose of this RFA is to support investigations of the effects of 
exposure to marijuana, the most commonly used illicit drug among 
teenagers in the United States, on the developing brain. There is now 
overwhelming evidence that the development of the nervous system 
continues well into adolescence and that different developmental epochs 
are defined by different (although overlapping) processes, such as 
neurogenesis, migration and pattern formation, differentiation, and 
establishment of connections and their refinement. A substantial 
literature exists on the consequences of acute and chronic marijuana 
exposure in adults, including measures of cognitive and behavioral 
effects, as well as some measures of alterations in brain function, 
primarily in the domains of learning and memory. There have been 
relatively few studies, however, of the effects of exposure to 
marijuana during development, when those areas that are known to be 
affected in adults are being sculpted by intrinsic and environmental 
influences (e.g., exposure to other drugs, stress, interactions with 
peers, parenting, neighborhood factors, and other social variables).  
Investigations in animal systems have provided considerable evidence 
concerning the mechanisms and sites of action of the psychoactive 
ingredients in marijuana, and methodologies are now available to 
describe in detail the development of these neural systems and, thus, 
the effects of exposure to marijuana on development.  

It is the intent of this RFA to encourage research on effects of 
marijuana exposure on the developing brain, at points along a continuum 
of development from the prenatal period through the transition to 
adulthood. The focus is on influences on brain biochemical, 
physiological, morphological, and functional parameters, and/or on 
cognitive, behavioral, and social outcomes resulting from such 
influences.  Human and nonhuman studies are sought.  Analyses of 
gender, as appropriate, are encouraged.  

RESEARCH OBJECTIVES

Background

A substantial literature exists on consequences of acute and chronic 
marijuana use in adults (e.g., various cognitive and behavioral 
outcomes, and some measurement of brain function).  However, this is 
not the case for preadolescents and adolescents, in either human or 
nonhuman animal samples. Available data from retrospective human 
studies show some associations between reported age of onset of 
marijuana use and cognitive outcomes as well as brain morphology.  
Studies on consequences of prenatal exposure to marijuana indicate 
effects in multiple developmental outcome areas as offspring progress 
through childhood and adolescence.    

It is widely accepted that the nervous system continues to develop well 
into adolescence, and that different developmental epochs are defined 
by different (although overlapping) processes, such as neurogenesis, 
migration and pattern formation, differentiation, and establishment of 
connections and their refinement.  Evidence also indicates that 
considerable plasticity endures into adulthood.  But very little is 
known about the consequences of marijuana exposure on the developing 
nervous system. Studies are needed to achieve increased understanding 
of the effects of marijuana on the developing brain, and the resulting 
behavioral manifestations of such effects. 

A critical aspect of this need for new knowledge relates to the 
specific timing of exposure; that is, the issue of how marijuana 
exposure affects brain development and resulting behavior as a function 
of when on the developmental continuum (from prenatal through 
adolescence) the exposure occurs.  Timing of exposure is not simply a 
matter of age, but importantly also relates to a point in a process of 
development.  Critical factors defining a point in a developmental 
process vary with the focus of the research; for example, in some cases 
developmental status may focus on neurological factors, in other cases 
neurological and neuroendocrine, and in still other cases 
neurocognitive, neuroendocrine, and social functioning.  

Preclinical, clinical, and epidemiologic approaches are appropriate for 
acquiring needed new knowledge.  For example, animal models of 
adolescence appropriate for the study of persistent effects of cannabis 
may contribute to improved understanding of influences on 
neurobehavioral and neuroendocrine development, and of compensatory 
control systems during adolescence.  These models may also permit 
investigation of questions related to long-term consequences of 
adolescent cannabis exposure on systems subserving plasticity, 
executive functions, and cognition.  Many topics pertaining to 
marijuana effects on the developing brain can be addressed by both 
animal and human studies, and in some cases by utilizing complementary 
animal-human samples.  Proposals based on analyses of existent data are 
acceptable for review if they address research questions relevant to 
the RFA.  Studies nested within epidemiologic samples have the 
potential to isolate pre-existing conditions prior to marijuana use 
from post-use consequences, and may facilitate examination of important 
research questions such as whether marijuana use differentially affects 
neurological function for youth at high- versus low-risk for drug 
abuse.  

Investigations of issues pertinent to this RFA face multiple 
methodological challenges.  Researchers have identified numerous study 
design and measurement considerations as important.  These include: 
pre-existing differences between marijuana users and non-users prior to 
exposure, the nature of normative brain development, polydrug exposure 
and patterns of drug use, family history factors, social context and 
co-occurring environmental conditions, and duration of abstinence.  
Studies examining marijuana effects in the context of co-occurring use 
of other licit and illicit substance are needed, and are appropriate 
for this RFA.  An additional consideration relates to gender analyses.  
In light of extensive data demonstrating gender differences in specific 
aspects of neurological, cognitive, and social development, and 
emerging evidence that the effects of drug exposure are affected by 
gender, it is also important for studies to incorporate gender analyses 
when appropriate and feasible.

Areas of Interest

This initiative encourages innovative and diverse research efforts to 
examine if, and how, marijuana exposure has demonstrable effects on the 
developing brain (whether shown in morphological alterations, 
differences in functional activation of specific brain areas, 
neurocognitive functioning, or behavioral manifestations).  Relevant 
broad topics of investigation include associations between marijuana 
exposure and changes in plasticity in key brain regions; influences of 
repeated marijuana use on development of cognitive, emotional, and 
motivational processes; impact of marijuana exposure on thresholds for 
drug and non-drug rewards; and differences in reinforcing effects of 
marijuana relative to when in adolescence the exposure occurs.  
Examples of more specific research areas and issues that would be 
appropriate for this RFA include, but are not limited to, the 
following:

o   Data from studies of normal development of the human brain strongly 
suggest that connections among a number of brain areas important in 
executive function, and particularly behavioral inhibition, are 
undergoing rapid development during adolescence.  Does exposure to 
marijuana during this developmental period alter the developmental 
trajectory of these brain areas and resulting behavioral 
manifestations?  Are any alterations induced by exposure influenced 
by timing of initiation and extent of exposure?  

o   A number of studies have demonstrated marijuana effects on learning 
and memory in adults.  Are there similar effects in younger 
individuals?  Does earlier exposure lead to more or less severe, or 
longer- or shorter-lasting effects, and if so, can these effects be 
related to an individual's age at the time of exposure?  Can effects 
be related to neurocircuitry?  

o   Does marijuana influence motivational and emotional states 
differentially as a function of when in development it is used?  How 
do such influences vary with amount, frequency, and duration of use?  
What are the dynamic bi-directional processes between marijuana use 
and motivational and emotional states?  

o   Are there identifiable neurobiological and/or behavioral/cognitive 
markers for those youth who progress from marijuana use to abuse, 
and to dependence?  Do these mechanisms differ as a function of when 
in the developmental process marijuana use is initiated?  

o   What characteristics identify youth who do not progress to marijuana 
abuse or dependence?  What neurobiological or cognitive mechanisms 
are involved in successful cessation of marijuana use?  

o   How do neuroendocrine, cognitive, and social changes related to 
pubertal status interact with marijuana use to produce effects on 
the developing brain?  

o   How does tobacco and alcohol use by youth (prior, concomitant, or 
subsequent to marijuana initiation) influence effects of marijuana 
on brain development and associated consequences?  What are the 
effects of co-occurring use of marijuana and other illicit drugs? 

o   How does marijuana use interact with mental health conditions that 
may emerge during adolescence (e.g., eating disorders, mood 
disorders, schizophrenia), and how do such interactions affect brain 
development and related behaviors?  What are the interactions of 
marijuana use with other co-occurring illnesses (e.g., HIV 
infection)?  

o   Some adolescents use marijuana in combination with medications 
prescribed for mental or physical health conditions.  What can be 
learned about the effects of marijuana on the developing brain and 
behavior by investigating the combined influences of marijuana and 
prescription drugs (e.g., medications for attention deficits, 
antiretroviral treatments for HIV infection)? 

o   Long-term cohort studies show associations between prenatal 
marijuana exposure and performance in multiple domains (e.g., 
memory, attentional processes, aspects of executive function). What, 
if any, additional neurodevelopmental manifestations are present? 
What brain development processes are involved in consequences of 
prenatal exposure?  Are those who were prenatally exposed 
differentially affected by use of marijuana, or other drugs, during 
childhood, pre-adolescence, or adolescence (e.g., behavioral, 
cognitive, and neurobiological outcomes, vulnerability to substance 
use disorders, and other mental health conditions)?  

o   How can marijuana ‘effects’ (subjective, performance, reinforcing) 
be characterized among adolescents, and how do these compare to 
those in adults?  For example, are adolescents more sensitive to 
subjective effects of marijuana along an appetitive – aversive 
continuum?  Given metabolically equivalent doses, do adolescents 
show enhanced reinforcing effects that may contribute to a greater 
vulnerability?  Are they differentially impaired on neurocognitive 
or performance measures relative to their adult counterparts?  Do 
adolescents respond as do adult subjects to drug-associated 
environmental cues that elicit reports of craving?  

o   Are long-term neuroadaptive changes seen in adolescents after 
repeated marijuana exposure?  How do neurobiological adaptations 
seen in adolescent subjects contribute to subsequent vulnerability?  
Does marijuana exposure change the threshold of some central 
motivational ‘barometer’ to shift responding for other rewards 
(including naturally-occurring, non-drug rewards, and rewards from 
other drug classes)?  

o   What are the consequences of repeated marijuana exposure for 
multiple domains of development?  For example, how does repeated 
marijuana abuse alter development of cognitive, emotional, or social 
processes?   Neurobiological substrates that may serve as markers, 
indicators, or mediators for changes in these trajectories could 
also be examined.  

o   Does marijuana use affect developmental shifting of circadian 
rhythms and related sleep behaviors in adolescence, and if so, how?  
What are the neurological implications?

o   Adolescence coincides with increased myelination in many regions of 
the brain, an important process that influences many domains of 
learning and behavior.  Does marijuana exposure have an impact on 
glial proliferation, function, or survival?   

o   Animal data have suggested that marijuana can negatively regulate 
stem cell proliferation in the adult hippocampus.  What are the 
potential changes in rates of neurogenesis in the adolescent brain 
relative to marijuana exposure?  How do these changes compare to 
those in adults?  

o   What are the pharmacokinetics and toxicokinetics of marijuana and 
THC in the developing fetus? 

o   What are the characteristics of molecular and biochemical marijuana-
induced alterations of critical substrates of drug abuse (e.g., 
enzymes, receptors, neurotransmitters, etc.) related to development, 
time course, and associated pharmacodynamics and toxicodynamics? 

Investigators interested in the topics of this RFA may also be 
interested in one or more of the following NIDA RFAs:  
DA-04-011, Animal Models of Adolescent Drug Abuse: 
Integrative Studies of Brain and Behavioral Development 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-DA-04-011.html); 
DA-04-009, Behavioral and Cognitive Processes Related to Adolescent Drug Abuse 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-DA-04-009.html); 
DA-04-014, Medications Development for Cannabis-Related Disorder 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-DA-04-014.html); 
DA-04-013, Prevention Research for the Transition to Adulthood 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-DA-04-013.html).

MECHANISMS OF SUPPORT

This RFA will use the NIH research project (R01) and the 
exploratory/developmental (R21) award mechanisms 
(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.  
The anticipated award date is September 30, 2004.  Applications that 
are not funded in the competition described in this RFA may be 
submitted as NEW investigator-initiated applications using the standard 
receipt dates for NEW applications described in the instructions to the 
PHS 398 application.

This RFA uses just-in-time concepts.  It also uses 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/nihgps_2001/part_i_1.htm.

FUNDS AVAILABLE 

NIDA intends to commit approximately $2 million in FY 2004 to fund 4-6 
new and/or competitive continuation grants in response to this RFA.  
For the R01, an applicant may request a project period of up to 5 years 
and a budget for direct costs of up to $500,000 per year.  APPLICATIONS 
REQUESTING A BUDGET THAT EXCEEDS $500,000 IN DIRECT COSTS IN ANY YEAR 
WILL BE RETURNED TO APPLICANTS WITHOUT REVIEW.  For the R21, the 
project period is 2 years and up to $275,000 in direct costs for the 
two-year period (http://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 NIDA 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:

Vincent L. Smeriglio, Ph.D.
Human Development Unit
Center on AIDS and Other Medical Consequences of Drug Abuse
National Institute on Drug Abuse/NIH/DHHS
6001 Executive Boulevard, Room 5198, MSC 9593
Bethesda, MD 20892-9593
Telephone: (301) 443-1801
Fax: (301) 480-4544
Email: vsmerigl@nida.nih.gov

o Direct your questions about peer review issues to:

Teresa Levitin, Ph.D.
Office of Extramural Affairs
National Institute on Drug Abuse/NIH/DHHS
6101 Executive Boulevard, Suite 220, MSC 8401
Bethesda, Maryland  20892-8401
Telephone:  (301) 443-2755
FAX:  (301) 443-0538
Email:  tlevitin@mail.nih.gov

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

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse/NIH/DHHS
6101 Executive Boulevard, Suite 242, MSC 8403
Bethesda, MD  20892-8403
Telephone:  (301) 443-6710
FAX:  (301) 594-6849
Email:  gf6s@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 NIDA 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:

Director
Office of Extramural Affairs
National Institute on Drug Abuse/NIH/DHHS
6101 Executive Boulevard, Suite 220, MSC 8401
Bethesda, MD  20892-8401
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 443-2755
FAX:  (301) 443-0538
Email:  tlevitin@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.

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/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/DHHS
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:

Director
Office of Extramural Affairs
National Institute on Drug Abuse/NIH/DHHS
6101 Executive Boulevard, Suite 220, MSC 8401
Bethesda, MD  20892-8401
Rockville, MD  20852 (for express/courier service)

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 assignments 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 unfounded 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 NIDA.  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 NIDA 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 the National Advisory Council on 
Drug Abuse

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.

(1) SIGNIFICANCE:  Please assess the extent to which the study aims are 
consistent with the goals of the RFA.  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?  Does 
the study address an important problem consistent with the goals of 
this RFA?

(2) 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?

(3) 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?

(4) 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)?

(5) 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).

ADDITIONAL REVIEW CONSIDERATIONS

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:    March 16, 2004 
Application Receipt Date:         April 16, 2004
Peer Review Date:                 July/August 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 SAFETY AND 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 Safety and 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 AMENDMENT 
"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.

HIV/AIDS COUNSELING AND TESTING POLICY FOR THE NATIONAL INSTITUTE ON 
DRUG ABUSE:  Researchers funded by NIDA who are conducting research in 
community outreach settings, clinical, hospital settings, or clinical 
laboratories and have ongoing contact with clients at risk for HIV 
infection, are strongly encouraged to provide HIV risk reduction 
education and counseling.  HIV counseling should include offering HIV 
testing available on-site or by referral to other HIV testing service 
for persons at risk for HIV infection including injecting drug users, 
crack cocaine users, and sexually active drug users and their sexual 
partners.  For more information see 
http://grants.nih.gov/grants/guide/notice-files/NOT-DA-01-001.html.

NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE 
ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS:  The National Advisory 
Council on Drug Abuse recognizes the importance of research involving 
the administration of drugs to human subjects and has developed 
guidelines relevant to such research.   Potential applicants are 
encouraged to obtain and review these recommendations of Council before 
submitting an application that will administer compounds to human 
subjects.  The guidelines are available on NIDA's Home Page at 
http://www.nida.nih.gov under the Funding, or may be obtained by 
calling (301) 443-2755.

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.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, RealPlayer, Video or Flash files, see Help Downloading Files.