CLINICAL USE OF MEDICATIONS TO TREAT ALCOHOLISM AND ALCOHOL-RELATED 
DISEASES

RELEASE DATE:  April 11, 2002

PA NUMBER:  PA-02-098

EXPIRATION DATE:  This PA expires on April 15, 2005, unless reissued.

National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
 (http://www.niaaa.nih.gov)

National Institute on Drug Abuse (NIDA)
 (http://www.nida.nih.gov)
 
THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE 

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is 
seeking research grant applications on the clinical use of medications 
for alcohol abuse/dependence and alcohol-related diseases. 
Investigations are needed on pharmacological agents that prevent or 
reduce alcohol intake by decreasing the alcohol craving/urge to drink 
and/or alleviating the negative symptoms associated with drinking 
(e.g., protracted withdrawal syndrome. Applications are also encouraged 
to develop and test agents for the treatment of acute alcohol 
withdrawal and alcohol intoxication.  Evaluations of pharmacological 
agents to clinically treat alcohol-induced diseases, such as alcoholic 
liver diseases, are encouraged as well.  In addition, applications can 
include the utilization of human laboratory paradigms to screen 
potential medications for subsequent phase 2 and 3 trials as well as to 
determine the actions of the medications.  All applications submitted 
in response to this program announcement should be conducted in humans.

RESEARCH OBJECTIVES

Background

During the past decade advances have been made in medications 
development to treat alcoholism (see comprehensive reviews by Garbutt 
et al., 1999; Swift, 1999; and Kranzler, 2000). The fruits of these 
efforts have been highlighted by the FDA approval of naltrexone, the 
first medication approved for alcoholism in the 50 years since the 
introduction of disulfiram. Advances have also been made in 
understanding the biological mechanisms underlying alcohol drinking 
behavior. For example, it is now known that multiple neurotransmitter, 
neuromodulator, and hormonal systems can alter alcohol intake and are 
either directly or indirectly involved in problematic drinking. These 
include opioid, serotonin, dopamine, gamma-aminobutyric acid (GABA), 
glutamate, neuropeptide Y (NPY), cannabinoid, and hypothalamic-
pituitary-adrenal (HPA) systems (Litten et al., 1996; Roberts and Koob, 
1997; Johnson and Ait-Daoud, 2000; Lallemand et al., 2001). This recent 
knowledge has led to many biological targets for testing novel 
pharmacological agents. 

To date, the two most promising and successful medications are 
naltrexone and acamprosate. Two important clinical trials of naltrexone 
(Volpicelli et al., 1992 and O'Malley et al., 1992) first demonstrated 
efficacy of naltrexone in alcohol dependent patients and contributed 
significantly to FDA approval of naltrexone. Although naltrexone is not 
a "magic bullet" for alcoholism treatment, it appears to have a 
moderate effect in reducing drinking, particularly reducing relapse to 
heavy drinking (Volpicelli et al., 1997; Anton et al., 1999; Morris et 
al., 2001; Heinala et al., 2001). Recent studies have suggested that 
patient compliance plays a significant role in the efficacy of 
naltrexone (Volpicelli et al., 1997; Chick et al., 2000; Monti et al., 
2001). Nonetheless, naltrexone may not be effective for all alcoholics 
(Kranzler et al., 2000; Krystal et al, 2001). Several studies are 
currently being funded to address many issues surrounding the clinical 
use of naltrexone such as how long should patients receive naltrexone; 
what is the optimal dose; what types of alcoholics respond best; what 
is the optimal combination with behavioral/psychosocial interventions; 
and can the efficacy of naltrexone be improved by combining it with 
other medications. Finally, nalmefene, another opioid antagonist, has 
also demonstrated effectiveness in preventing relapse to heavy drinking 
in alcohol- dependent patients (Mason et al., 1999). 

Acamprosate has been studied extensively in Europe and is currently 
approved for alcoholism treatment in 37 countries. Sixteen controlled 
clinical trials have been conducted across 11 European countries 
involving more than 4,600 alcohol dependent patients. The studies have 
consistently shown that individuals treated with acamprosate are more 
likely to complete treatment, have longer times to their first drink, 
have greater abstinence rates, and demonstrate longer cumulative 
abstinence durations than placebo-treated patients (Mason and Ownby, 
2000). A 21-site trial of acamprosate has recently been completed in 
the US with 601 alcohol dependent patients. Results of this trial have 
been submitted to the FDA as part of a New Drug Application to obtain 
US approval. Acamprosate's mechanism of action has yet to be 
definitively identified, although several studies suggest that it may 
modulate activity of the glutamate system (Littleton, 1995; Spanagel 
and Zieglgansberger, 1997). 

The serotonergic system has also been implicated in drinking behavior. 
The serontonin3 (5-HT3) receptor has been shown to regulate release of 
dopamine in the mesolimbic area, particularly in the nucleus accumbens. 
Ondansetron, a 5-HT3 antagonist, has been demonstrated to reduce desire 
to drink in humans and to augment stimulant and sedative effects of 
alcohol (Johnson, 1993; Swift et al., 1996). A 12-week dosage trial of 
ondansetron has recently been completed in early onset alcoholics and 
late onset alcoholics (Johnson et al., 2000b). Ondansetron reduced 
frequency and quantity of alcohol consumption in early onset 
alcoholics, but not in the late onset alcoholics. Interestingly, a 
preliminary study combining ondansetron and naltrexone showed that the 
combination reduced alcohol craving and enhanced drinking outcome to a 
greater extent than had each demonstrated alone (Johnson et al., 2000a; 
Ait-Daoud et al., 2001). 

Results of selective serotonin reuptake inhibitors (SSRIs) in human 
alcohol trials have been inconsistent (Pettinati, 1996, Kranzler, 
2000). Recent data, however, suggest that subpopulations of alcohol 
dependent patients respond differentially to the SSRIs. For example, 
Kranzler et al. (1996) and Pettinati et al. (2000) showed that higher-
risk/severity type B alcoholics had less favorable treatment outcome to 
SSRIs than lower-risk/severity type A alcoholics. Cornelius and 
colleagues (1997) found that fluoxetine reduced depressive symptoms and 
alcohol intake in severe inpatient populations of alcoholics with major 
depression and suicide risk. In contrast, Pettinati et al. (2001) and 
McGrath (1998) reported that fluoxetine and sertraline were no better 
than placebo in improving depression and reducing drinking in a less 
severe population of depressed alcoholics. 

Since all the medications discussed above produce small to medium 
effects to reduce or prevent drinking, developing and evaluating new 
and more potent medications remain a high priority. Several promising 
pharmacological agents could lead to clinical testing. These include, 
but are not limited to, memantine, a non-competitive NMDA antagonist 
(Holter et al., 1996); kudzu and its purified active components (e.g., 
puerarin) (Keung and Vallee, 1993; Lin et al., 1996); corticotropin-
releasing factor (CRF) antagonists (Bell et al., 1998; Le et al., 2000; 
Richter et al., 2000); opioid subtype receptor antagonists such as 
delta2 antagonist naltriben (June et al., 1999); 6-beta naltrexol, an 
active metabolite of naltrexone (Rukstalis et al., 2000); synthetic 
neurosteroids (Morrow et al., 1999); 1-aminocyclopropanecarboxylic acid 
(ACPC), a NMDA partial agonist (Stromberg et al., 1999); and FG 5974 
(and its analogues), a 5-HT1A agonist/5-HT2A antagonist (Roberts et al., 
1998). 

For more than two decades, benzodiazepines have been the most widely 
used medication for pharmacological management of acute alcohol 
withdrawal. They have consistently been demonstrated to assuage many 
symptoms of withdrawal (Mayo-Smith, 1997). Recent studies have focused 
on benzodiazepine dosing strategies. For example, a "loading dose" 
technique in which benzodiazepines are given every 1 or 2 hours until 
withdrawal symptoms subside, appears effective in preventing over- and 
under-dosing of medication (Wartenberg et al., 1990; Sullivan et al., 
1991; Saitz et al., 1994). Yet in spite of their benefits, 
benzodiazepines have adverse effects including memory impairment, 
drowsiness, lethargy, and cognitive problems. 

Finally, progress has been made in elucidating the mechanisms of 
alcohol-induced organ damage. In particular, several primary factors 
underlying the pathogensis of alcoholic liver disease have been 
identified including cytokines and reactive oxygen species (ROS) 
(Tsukamoto and Lu, 2001). For example, the administration of antibodies 
against the proinflammatory tumor necrosis factor (TNF)-? attenuated 
alcohol-induced liver injury in rats (Iimuro et al., 1997). A later 
study showed an absence of alcohol liver injury in knockout mice 
missing the TNF receptor 1 (Yin et al., 1999). ROS are generated by the 
metabolism of alcohol and can also cause damage to the liver (Tsukamoto 
and Lu, 2001). ROS are quickly inactivated by antioxidants, such as 
glutathione and vitamins A and E. Antioxidants, such as S-adenosyl-L- 
methionine (SAMe), have also been shown to reduce alcohol-induced liver 
injury in animals. Potential new treatments of alcoholic liver disease 
include antioxidants, such as SAMe and vitamin E; as well as other 
types of agents including phosphatidylcholine, a phospholipid; 
pirfenidone, a new broad- spectrum anti-fibrotic agent; and metformin, 
an insulin-sensitizing agent (Lieber, 2001; Miric et al., 2001; 
Tsukamoto and Lu, 2001).

[The full references for scientific literature cited in this RFA may be 
obtained from Dr. Joanne Fertig, whose contact information may be found 
in the section WHERE TO SEND INQUIRIES, below.] 

Specific Areas of Interest

NIAAA is committed to the development and assessment of pharmacological 
agents to treat alcohol use disorders as well as the more prevalent and 
severe medical conditions associated with chronic drinking. 
Pharmacological agents of interest for phase 2, 3, and 4 clinical 
testing and for human laboratory testing can be categorized by function 
as follows: 

- Agents to decrease craving or urge to drink. 

- Agents to attenuate negative symptoms of alcoholism (e.g.,"protracted 
withdrawal" symptoms). 

- Agents to diminish drinking by alleviating co-occurring psychiatric 
pathology and other drug use.

- Agents to treat alcohol-associated liver disease and other end-organ 
diseases, such as pancreatitis, cardiomyopathy, and bone disease. 

- Agents to treat acute alcohol withdrawal.

- Agents to induce sobriety in intoxicated individuals

Many important clinical priorities and issues exist for these classes 
of pharmacological agents and are identified, but not limited, to the 
following: 

- New and existing pharmacological agents and combination of those 
agents, need to be identified and evaluated in conjunction with 
behavioral therapies for alcoholism treatment. Optimal dosing regimens 
and length of treatment need to be established. Although NIAAA has 
supported projects on the efficacy of the opioid antagonist naltrexone, 
the therapeutic potential of other pharmacological agents in the opioid 
class is a current research priority. In addition to opioid 
antagonists, the therapeutic potential of other types of agents needs 
to be assessed. Among these are agents that interact with the 
serotonergic, dopaminergic, glutamatergic, GABAergic, NPY, cannabinoid, 
and HPA systems as well as herbal preparations.

- Development of pharmacological agents to attenuate negative symptoms 
of chronic drinking, sometimes referred to as the "protracted 
withdrawal" syndrome. Research on potential pharmacological treatment 
of this phenomenon has been quite limited, due to failure to specify 
cardinal symptoms associated with sustained sobriety by alcoholics. 
Research is needed to establish operational definitions of this event 
as is research on agents to reduce the severity of protracted symptoms. 

- Pharmacological agents need to be identified and their efficacy 
evaluated in special populations previously understudied in medication 
trials. Examples of such populations of interest are alcohol 
abusing/dependent individuals in the criminal justice system, health 
professions, adolescents, the elderly, and minorities including persons 
of African heritage and Hispanic/Latino culture, Native 
Americans/Alaskan Natives, Asian Americans, and Native Hawaiian and 
Pacific Island Populations. 

- Development of pharmacological agents to treat alcoholics with 
comorbid psychopathology such as bipolar disorder, schizophrenia, and 
anxiety disorders including social phobia and post-traumatic stress 
disorder. The co-occurrence of psychiatric problems among alcoholics in 
treatment is frequent. Comorbidity, however, is generally associated 
with a poorer treatment prognosis as well as high dropout rates and 
poor compliance. Research needs to include assessment of changes in the 
comorbid psychopathology as well as changes in drinking outcomes.

- Factors influencing clinical efficacy of medications to treat alcohol 
abuse and dependence can be identified using human laboratory 
behavioral pharmacology paradigms. Prior to beginning phase 2 clinical 
trials, potential medications can be screened in the laboratory to 
determine the following: 1) the medication's impact to reduce craving 
for alcohol and/or to diminish the negative symptoms of drinking; 2) 
likelihood of adverse events, especially in the presence of alcohol; 3) 
pharmacokinetics for medication combinations; and 4) optimal dosing 
regimens. Studies are sought which develop and expand use of these 
human laboratory paradigms. 

- Development of medications to treat alcoholic liver diseases and 
other alcohol-related, end-organ diseases. These may include agents 
that inactivate excess ROS or alter the production or clearance of 
cytokines. In reducing the high mortality from alcoholic hepatitis and 
cirrhosis, potential medications that prevent necrosis/inflammation and 
avert or reverse the progression of fibrosis are of high priority. 
Other potential agents include those that are effective in treating 
alcohol-induced portal hypertension, pancreatitis, and bone disease. 

- Development of alternative medications to treat acute alcohol 
withdrawal.  Also, assuming the "kindling" effect (the severity of 
withdrawal symptoms increases after repeated withdrawal episodes) has 
clinical relevance (Becker, 1998), can kindling be effectively curbed 
by medications to treat withdrawal? 

Supported pharmacological investigations should include use of 
appropriate control groups, adequate sample sizes, and employment of 
proper statistical analyses. In evaluating the efficacy of all 
pharmacological agents, it is important to identify subtypes of 
alcoholics particularly amenable to pharmacological treatment as well 
as to explore integration of pharmacotherapy with behavioral and verbal 
therapies. In addition, the experimental treatments should be carefully 
described, and diagnostic and outcome instruments should reflect state-
of-the-art alcoholism assessment. While early clinical studies may 
employ highly homogeneous samples in a single setting, it is desirable 
in later-stage research to have greater heterogeneity in samples and 
sites. Efficacy studies also need to measure compliance with the 
pharmacological intervention and adequately verify self-reports. 
Finally, after completion of the active treatment of the clinical 
trial, it is recommended that subjects be followed-up for at least six 
months. 

MECHANISM(S) OF SUPPORT 

This PA will use the NIH research project grant (R01) small grant (R03) 
and Exploratory/developmental grant (R21) award mechanism.  As an 
applicant, you will be solely responsible for planning, directing, and 
executing the proposed project. The total project period for a research 
project grant (R01) application submitted in response to this Program 
Announcement may not exceed 5 years.  Exploratory/developmental grants 
(R21) are limited to 3 years for up to $100,000/year for direct costs. 
(See Program Announcement PA-99-131, "NIAAA Exploratory/Developmental 
Grant Program," https://grants.nih.gov/grants/guide/pa-files/PA-99-
131.html, for a complete description of the R21 mechanism.)    

Under the NIAAA Small Grant mechanism (R03) applicants may request 
either $25,000 or $50,000 in direct costs per year for up to two years.  
These awards are not renewable; however, a no-cost extension
of up to one year may be granted to the grantee institution prior to 
expiration of the project period. Before completion of the R03, 
investigators are encouraged to seek continuing support for research 
through a research project grant (R01).  (See Program Announcement PA-
99-098, "NIAAA Small Grant Program," 
https://grants.nih.gov/grants/guide/pa-files/PAR-99-098.html, for a 
complete description of the R03 mechanism.)

This PA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see https://grants.nih.gov/grants/funding/modular/modular.htm).   
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.

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 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 your inquiries concerning this PA and welcome the 
opportunity answer questions from potential applicants.

o Direct your questions about scientific issues related to alcohol 
research to:

Joanne B. Fertig, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulvard, Suite 505 MSC 7003
Bethesda, MD 20892-7003
For express mail use:
Rockville, MD 20852
Telephone: (301) 443-0635
Fax: (301) 443-8774
Email: jfertig@niaaa.nih.gov

o Direct your questions about scientific issues related to research 
involving drug abuse or drug abusing populations to: 

Jamie Biswas, Ph.D.
Chief, Medications Research Grants Branch
Division of Treatment Research & Development
National Institute on Drug Abuse
6001 Executive Boulevard., Room. 4123, MSC 9551
Bethesda, MD 20892-9551
Telephone: (301) 443-8096
Fax: (301) 443-9649
Email: jb168r@nih.gov
 
o Direct your questions about financial or grants management matters 
to:

Judy Simons
Chief, Grants Management Office
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 504
6000 Executive Boulevard, MSC 7003
Bethesda, MD 20892-7003
(301) 443-4704 (telephone)
(301) 443-3891 (fax)
email:  jsimons@willco.niaaa.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at https://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this 
program announcement will be accepted at the standard application 
deadlines, which are available at 
https://grants.nih.gov/grants/dates.htm.  Application deadlines are also 
indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at 
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
https://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER 
YEAR: Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIAAA staff member who 
has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following 
steps:

1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types. Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be received by or mailed 
before the receipt dates described at 
https://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR 
will not accept any application in response to this PA that is 
essentially the same as one currently pending initial review unless the 
applicant withdraws the pending application.  The CSR will not accept 
any application that is essentially the same as one already reviewed.  
This does not preclude the submission of a substantial revision of an 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review 
group convened in accordance with the standard NIH peer review 
procedures (http://www.csr.nih.gov/refrev.htm) will evaluate 
applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority 
score
o Receive a second level review by the 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 your 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 your application's overall score, weighting them 
as appropriate for each application.  Your 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, 
you may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

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

(2) APPROACH:  Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project?  Do you acknowledge potential problem areas and 
consider alternative tactics?

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

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

(5) ENVIRONMENT:  Does the scientific environment in which your 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, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  The adequacy of the proposed protection for humans or the 
environment, to the extent they may be adversely affected by the 
project proposed in the application.

INCLUSION:  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 included in the section on Federal Citations, below)

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

OTHER REVIEW CRITERIA:  

AWARD CRITERIA

Applications submitted in response to a PA will compete for available 
funds with all other recommended applications.  The following will be 
considered in making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND 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 Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
https://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 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2
001.htm.   The amended policy incorporates: the use of an NIH 
definition of clinical research; updated racial and ethnic categories 
in compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS:  The NIH maintains a policy that children (i.e., individuals 
under the age of 21) must be included in all human subjects research, 
conducted or supported by the NIH, unless there are scientific and 
ethical reasons not to include them. This policy applies to all initial 
(Type 1) applications submitted for receipt dates after October 1, 
1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the inclusion of children as 
participants in research involving human subjects that is available at 
https://grants.nih.gov/grants/funding/children/children.htm. 

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

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

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

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 a 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 PA 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 No. 93.273, and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284) and administered under NIH grants policies described 
at https://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

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.
https://grants.nih.gov/grants/guide/pa-files/PA-02-015.html. 

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, Audio or Video files, see Help Downloading Files.