RELEASE DATE:  February 24, 2004

PA NUMBER:  PA-04-067

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date for these 
mechanisms. The non-AIDS portion of this funding opportunity for these mechanisms 
expires on the date indicated below. Other mechanisms relating to this announcement 
will continue to be accepted using paper PHS 398 applications until the stated 
expiration date below, or transition to electronic application submission. Parent 
R03 (PA-06-180) and R21 (PA-06-181) funding opportunity announcements have been 
issued for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter. Applications relating to R33 and R34 activities 
must be in response to NIH Institute/Center (IC)-specific announcements.

EXPIRATION DATE for R03 and R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R03 and R21 AIDS and AIDS-Related Applications: May 2, 2006 
EXPIRATION DATE for All R01 Applications: January 30, 2007, unless re-issued.

Department of Health and Human Services (DHHS)

National Institutes of Health (NIH)

National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
National Institute on Drug Abuse (NIDA)

93.279 (NIDA)

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

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the 
National Institute on Drug Abuse (NIDA) are seeking research grant 
applications on pharmacological treatment for patients with alcohol use 
disorder (AUD) and a comorbid substance use disorder (SUD).  Substance 
use disorder may include the abuse/dependence of heroin, prescription 
narcotics, cocaine, methamphetamine and other stimulants, 
hallucinogens, sedative hypnotics, marijuana, and other substances of 
abuse.  Alcoholic abuse/dependent patients may have a co-occurring 
nicotine dependence, but must also meet the criteria for other types of 
SUD.  Research on the specific treatment needs of this population is in 
early stages, and thus well-designed studies are needed.  In 
particular, it is important to understand how the effects of treating 
one disorder affects the outcome for the other disorder.  The 
intervention strategy to treat one or both comorbid conditions might 
depend on the type of comorbidity as well as the subtype of comorbid 
AUD/SUD patient.  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 for the treatment of comorbid AUD and SUD.  All 
applications submitted in response to this program announcement should 
be conducted in humans.  In addition, all applicants are encouraged to 
evaluate the interactions among alcohol, the abused substance and the 
medication under investigation.



Alcohol abuse and dependence commonly occurs in subjects who suffer 
from SUD and  patients with AUD often have SUD, for example, as many as 
90 percent of cocaine addicts have a problem with alcohol in both 
treatment and community settings. Patients suffering from both 
disorders often have poorer treatment outcome and are more likely to 
drop out of treatment. Unfortunately, effective pharmacological 
treatments have yet to be established for the various conditions of 
comorbid AUD and SUD. 

In developing effective treatment strategies for each substance of 
abuse, one may need to take into account the physiological and 
psychological alternations that can occur from a drug-alcohol 
interaction.  For example, ingestion of alcohol and cocaine can produce 
a new metabolite, cocaethylene, which can increase craving as well as 
increased heart rate.

Some progress has been made in treating patients with a concurrent 
alcohol and cocaine dependence.  Carroll et al. (1998) reported that 
disulfiram combined with outpatient psychotherapy enhanced treatment 
retention and increased the duration of abstinence from both alcohol 
and cocaine use.  In a preliminary report, it was found that supervised 
disulfiram reduced both alcohol and cocaine intake in patients dually 
diagnosed with cocaine dependence and alcohol abuse/dependence. 
Interestingly, naltrexone at doses of 50 mg/day has been reported 
ineffective in treating comorbid alcohol and cocaine use disorders. 
Nevertheless, in a preliminary report in 1999, alcohol and cocaine 
dependent patients treated with higher doses of naltrexone (150 mg/day) 
reduced both their frequency and amount of alcohol and cocaine intake.  
Studies are underway to test the efficacy of 150 mg of naltrexone daily 
and also to evaluate the effectiveness of the combination of naltrexone 
and disulfiram in this population.

Little research has been conducted on alcoholics with a comorbid opioid 
addiction.  In an early study it was reported that disulfiram given to 
alcoholic methadone patients reduced their alcohol intake.  However, 
new studies are needed to test newer medications such as buprenorphine 
for opioid dependence and naltrexone and acamprosate for alcoholism.   
In summary, research to evaluate effective combined pharmacological and 
behavioral treatments for patients diagnosed with AUD and SUD is in 
very early stages. The purpose of this program announcement is to 
stimulate state-of-the-art research to evaluate promising 
pharmacological treatments across a wide population of comorbid AUD and 
SUD subjects.  

Specific Areas of Interest

A wide variety of research opportunities exist for advancing the 
treatment of this understudied population.  Research topics include, 
but are not limited to:   

Evaluate the efficacy of established and novel pharmacological agents 
for AUD patients with a comorbid SUD.  

Evaluate pharmacotherapies for the treatment of AUD and SUD in patients 
with other co-morbid psychiatric disorders. 

Appropriate combination and sequencing of pharmacological and 
behavioral therapies for patients suffering from concurrent AUD and SUD 
disorders is needed.  In addition, optimal dosage and duration of 
treatment needs to be established for each medication.

Determine the optimal integration of pharmacological agents with 
behavioral therapies for concurrent AUD and SUD. 

Determine if outcome of pharmacological treatment of AUD patients 
suffering from comorbidity is different than that of non-comorbid 
patients or different as a function of gender.

Establish if the treatment of AUD or SUD improves or affects the 
outcome for the other comorbid psychiatric disorder. 

Determine if treatment for AUD and SUD should be conducted 
simultaneously or sequentially. 

Determine if the chronology of onset of the comorbid condition (e.g., 
primary versus secondary AUD) can influence treatment outcome and alter 
treatment strategy.

Evaluate pharmacological treatments for comorbidity in special 
populations including minorities, women, the elderly, adolescents, and 
those in the criminal justice system. 

Develop techniques to enhance treatment compliance in patients with 
comorbid AUD and SUD.  

Identify factors influencing the safety and clinical efficacy of 
medications for the treatment of AUD and SUD, 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 
and/or to diminish the negative symptoms of addiction; 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. 


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.

This PA uses just-in-time concepts.  It also uses the modular budgeting 
as well as the non-modular budgeting formats (see  
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


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


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.


The issue of safety of the three-way interaction of alcohol, the abused 
substance and the medication under investigation should be addressed in 
the application. The application should demonstrate (through pilot 
studies and /or citations of published data or presentation of 
unpublished data) that no serious adverse events would be expected from 
the co administration of alcohol, the abused substance and the 
medication under investigation. Serious adverse events (SAEs) are 
defined as any medical occurrence that results in death; is life-
threatening; requires inpatient hospitalization or prolongation of 
existing hospitalization; creates persistent or significant 
disability/incapacity, or a congenital anomaly/birth defects.


We encourage your inquiries concerning this PA and welcome the 
opportunity to answer questions from potential applicants.  Inquiries 
may fall into two areas:  scientific/research and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Charlene E. Le Fauve, Ph.D.
Division of Treatment and Recovery Research
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane
Bethesda, MD 20892-9304
For express mail use:
Rockville, MD 20852-1705
Telephone: (301) 402-9401
Fax: (301) 443-8774

Ivan D. Montoya, M.D., M.P.H. 
Medications Research Grants Branch 
Division of Treatment Research and Development
National Institute on Drug Abuse 
6001 Executive Blvd. 
Bethesda, MD 20892-9551 
Phone: (301) 443-8639 
Fax: (301) 443-2599 

o Direct your questions about financial or grants management matters 

Judy Fox (formerly Simons)
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane
Bethesda, MD 20892-9304
(For express mail use:
Rockville, MD 20852-1705)
Telephone: (301) 443-2434

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse 
6001 Executive Boulevard, Room 3131 MSC 9541 
Bethesda, Maryland 20892-9541 
Telephone: 301-443-6710 


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 The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form. The PHS 398 is available 
at in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email:

The title and number of this program announcement must be typed on line 
2 of the face page of the application form and the YES box must be 

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

Applications requesting up to $250,000 per year in direct costs must be 
submitted in a modular budget grant format.  The modular budget 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 includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at

YEAR: Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIH staff member 
within one of NIH institutes or centers who has agreed to accept 
assignment of the application.   

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

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 mailed on or before the 
receipt dates described at 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 
unfunded version of an application already reviewed, but such 
application must include an Introduction addressing the previous 

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.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.   Appropriate scientific review 
groups convened in accordance with the standard NIH peer review 
procedures ( will evaluate 
applications for scientific and technical merit.  

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

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 
o Receive a written critique
o Receive a second level review by the appropriate national advisory 
council or board  


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 
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 

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

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

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

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).
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 will be assessed.  Plans for the recruitment and 
retention of subjects will also be evaluated. (See Inclusion Criteria 
in the sections on Federal Citations, below).

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.  


SHARING RESEARCH DATA: Applicants requesting more than $500,000 in 
direct costs in any year of the proposed research are expected to 
include a data sharing plan in their application. The reasonableness of 
the data sharing plan or the rationale for not sharing research data 
will be assessed by the reviewers. However, reviewers will not factor 
the proposed data sharing plan into the determination of scientific 
merit or priority score. 

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


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


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.

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:  

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

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 

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 
a complete copy of the updated Guidelines are available at
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 

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 

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

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

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.

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 
( 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

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 

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.273 (NIAAA) and 93.279 (NIDA), 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  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 

Weekly TOC for this Announcement
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