Full Text AA-94-006

MEDICATIONS DEVELOPMENT FOR ALCOHOL-RELATED PROBLEMS

NIH GUIDE, Volume 22, Number 45, December 17, 1993

RFA:  AA-94-006

P.T. 34

Keywords: 
  Alcohol/Alcoholism 
  Treatment, Medical+ 
  Biology, Cellular 
  Chemotherapeutic Agents 


National Institute on Alcohol Abuse and Alcoholism

Application Receipt Date:  April 22, 1993

PURPOSE

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
seeking research grant applications to develop medications for the
treatment of alcoholism and other alcohol-related problems.  This
Request for Applications (RFA) deals with a range of pharmacological
agents at various stages of development, ranging from basic research
on the cellular and molecular mechanisms of alcohol-related problems
leading to identification of potential therapeutic targets and the
development of prototypic agents to testing drug efficacy in animal
and human subjects.  It also solicits research on clinical issues
surrounding use of medications in the treatment of alcoholism.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Medications Development for Alcohol-Related Problems, is related to
the priority areas of alcohol abuse reduction and alcoholism
treatment.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0, or Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone
202-783-3238).

ELIGIBILITY

Applications may be submitted by domestic and foreign, public and
private, non-profit and for-profit organizations, such as
universities, colleges, hospitals, research institutes and
organizations, units of State or local governments, and eligible
agencies of the Federal government.  Women and minority investigators
are encouraged to apply.  Foreign institutions are not eligible for
First Independent Research Support and Transition (FIRST) Awards
(R29).

MECHANISMS OF SUPPORT

Research support may be obtained through applications for a research
project grant (R01) or FIRST (R29) Award.  Applicants for R01s may
request support for up to five years.  In FY 1992, the average total
cost per year for new R01s funded by NIAAA was approximately
$200,000.  Because the nature and scope of the research proposed in
response to this RFA may vary, it is anticipated that the size of an
award will vary also.  FIRST Award applications must be for five
years.  Total direct costs for the five-year period may not exceed
$350,000 or $100,000 in any one budget period.  FIRST Awards cannot
be renewed, but grantees may apply for R01 support to continue
research on the same topics.

Potential applicants for FIRST Awards should obtain copies of the
FIRST program announcement (revised September 1993) from the National
Clearinghouse for Alcohol and Drug Information, P.O. Box 2345,
Rockville, MD 20852, telephone:  301-468-2600 or 1-800-729-6686.
Program project grants (P01) will not be accepted for this RFA.

Applicants may submit Investigator-Initiated Interactive Research
Project Grants (IRPGs).  Interactive Research Project Grants require
the coordinated submission of related research project grant (R01)
and, to a limited extent FIRST Award (R29) applications from
investigators who wish to collaborate on research, but do not require
extensive shared physical resources.  These applications must share a
common theme and describe the objectives and scientific importance of
the interchange of, for example, ideas, data, and materials among the
collaborating investigators.  A minimum of two independent
investigators with related research objectives may submit concurrent,
collaborative, cross-referenced individual R01 and R29 applications.
Applicants may be from one or several institutions.  Further
information on these and other grant mechanisms may be obtained from
the program staff listed under INQUIRIES.

FUNDS AVAILABLE

It is estimated that up to $2 million will be available for
approximately 8 to 10 grants under this RFA in FY 1994.  This level
of support is dependent on the receipt of sufficient number of
applications of high scientific merit.  Although this program is
provided for in the financial plan of NIAAA, the award of grants
pursuant to this RFA is also contingent upon the availability of
funds for this purpose.  The earliest possible award date is
September 30, 1994.

RESEARCH OBJECTIVES

Over the past decade, interest in pharmacologic treatment of alcohol
dependency has burgeoned in response to the growing knowledge of
cellular and molecular mechanisms of alcohol seeking behavior and its
associated biomedical consequences.  As a result, a rich array of
potentially useful pharmacological agents has been identified.  The
NIAAA has an interest in the development and assessment of
pharmacologic agents to address a number of medical, physiological,
and psychological effects of alcohol.  Such agents can be categorized
by function as follows:

o  Agents to decrease the desire to drink by attenuating alcohol
craving and blocking the euphoric effect (reward) derived from
drinking alcohol;

o  Agents that render drinking an aversive experience;

o  Agents to alleviate acute alcohol withdrawal;

o  Agents to treat "protracted withdrawal" symptoms;

o  Agents to diminish drinking by reducing co-occurring psychiatric
pathology and drug use;

o  Agents to induce sobriety in intoxicated individuals; and

o  Agents to treat alcohol-associated liver disease, other end-organ
diseases, such as pancreatitis, gastritis, etc., and neurologic
dysfunction and disease.

Within each of these classes of pharmacological agents, important
clinical issues need to be addressed.  Examples of areas for further
clinical research on medications development and testing include:

o  Agents to attenuate alcohol drinking behavior and prevent relapse.
At this time the most promising agent is naltrexone, an opioid
antagonist.  Two recent clinical studies have shown that
alcohol-dependent subjects treated with naltrexone engage in drinking
on fewer days, report less craving for alcohol, suffer fewer
relapses, and more readily cease drinking after one or two drinks.
Several projects on the efficacy of naltrexone are now being
supported by NIAAA.  Further research is needed to assess
naltrexone's effectiveness in more diverse clinical settings and
among varying subtypes of alcoholics.  The therapeutic potential of
other pharmacologic agents in the opioid class is also a current
research issue.  In addition to opioid antagonists, the therapeutic
potential of serotonergic, dopaminergic, and GABAergic agents also
need to be evaluated.  Finally, new types of pharmacologic agents
need to be identified and tested, particularly agents that bind to
specific receptor subtypes that deal with the motivational and
euphoric effects of excessive alcohol intake.

o  Development of pharmacologic agents to treat "protracted
withdrawal."  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 provide operational definitions of these phenomena as is
research on agents to reduce them.

o  Exploration of potential roles of antidepressive and anxiolytic
medications in treating alcoholics with comorbid psychiatric
disorders.  The co-occurrence of psychiatric problems among
alcoholics in treatment is frequent.  Comorbidity is generally
associated with a poorer treatment prognosis as well as high dropout
and poor compliance. Research needs include development and
assessment of newer antidepressive and anxiolytic medications and
demonstration of effects of treatment of co-occurring disorders on
drinking outcome.

o  Mechanisms of alcohol intoxication and development of a clinically
useful antagonist of alcohol intoxication.  A significant number of
people die each year from alcohol overdoses.  In order to effectively
treat this problem, medications developed based on the mechanisms of
the depressant effects of alcohol are needed.  Since death from
alcohol overdoses results from respiratory arrest, those depressed
mechanisms in the brain stem related to respiration would be of
particular interest.  Research to develop medications to alleviate
this life-threatening condition is needed, particularly in emergency
room settings.

o  Development of medications to improve cognitive dysfunction in
alcoholic dementia/Korsakoff's psychosis.  Progress in this area
would lead to enrichment in quality of life of alcoholics as well as
reduction in costs of long-term institutionalization.  Recent studies
have shown that serotonin reuptake inhibitors can improve memory to a
clinically meaningful degree in some patients with alcohol induced
amnesia.  Further research is needed on the development of
pharmacologic cognitive enhancers and transplantation procedures.

o  Development of medications to treat alcoholic liver diseases and
other alcohol-related, end-organ diseases.  In reducing the high
mortality from alcoholic hepatitis, potential medications include
those which effect the production or clearance of cytokines, prevent
other causes of necrosis/inflammation, and avert the progression of
fibrosis.  Other potential agents are those with potential utility in
the treatment of portal hypertension and alcohol-induced pancreatic
disease.

In addition, research is needed on broad clinical issues such as
strategies for enhancing patient compliance and identification of
possible subtypes of alcoholics who might respond most favorably to
alternative pharmacologic agent. Some examples of such research areas
are as follows:

o  Determination of appropriate medicational strategy based on
severity of acute alcohol withdrawal.  Research is needed on the
safety and efficacy of non-pharmacological treatment of alcohol
withdrawn.  With respect to pharmacological management of alcohol
withdrawal, it is important to define the most appropriate agents, as
well as the optimal dosing regimen.

o  Enhancement of patient compliance for medications, especially
disulfiram.  Utility of disulfiram is often diminished due to
discontinuance of the medication by the patient.  Research is needed
to develop and evaluate techniques for increasing patient compliance.

In order to find the most efficacious agents to treat the problems
listed, more basic research using animals models is needed on the
cellular and molecular mechanisms by which alcohol acts.  The
objectives of research proposals should lead directly to the
development of prototypic agents with clinical potential.

Examples of areas for further research:

o  Mechanisms of alcohol-seeking behavior.  Understanding why some
people drink uncontrollably, while others do not is a primary issue
for research.  Research is needed to understand what neuroreceptors
subtypes in the brain underlie a vulnerability for developing
alcoholism, are altered by the presence of alcohol, are modified
after chronic exposure, and are augmented or diminished by
environmental stimuli such as sensory cues and stress.  Prime
emphasis should be given to identifying potential agents that reduce
alcohol-seeking behavior.

o  Research on genetic factors.  To provide new targets for
pharmacological intervention, research is needed on genetic factors
predisposing to alcoholism (in humans) or genes influencing alcohol
consumption, sensitivity, tolerance, dependence, or other relevant
responses to alcohol (in animals).  Products of these identified
genes will be the targets for which new drugs can be developed.

o  Mechanisms of aversive properties of alcohol.  Consumption of
alcohol is normally self-regulating, in part due to its aversive
properties.  In an attempt to use these properties as a potential
therapeutic strategy, research is needed to understand aversion to
alcohol based on its taste and pharmacological effects, how the
strength of the aversion changes with chronic exposure, and how the
aversion could be strengthen to reduce alcohol consumption.  Such
research should address how these properties alter the efficacy of
medications that alter alcohol-seeking behavior.

o  Mechanisms of alcohol intoxication.  A significant number of
people die each year from drug overdoses.  In order to effectively
treat this problem, drugs based on the mechanisms of the depressant
effects of alcohol are needed.  Since death from overdoses results
from respiratory arrest, those depressed mechanisms in the brain stem
related to respiration would be of particular interest.

o  Mechanisms of alcohol dependence.  Psychological and physical
dependence on alcohol are presumed to contribute to continued
drinking and relapse.  Understanding the cellular and molecular
mechanisms of craving for alcohol after chronic use and how it might
be reduced is needed.  In addition, further knowledge is required of
the mechanisms of acute alcohol withdrawal and protracted withdrawal
symptomatology, such as anxiety, and the relationship between the
severity of withdrawal and the degree of alcohol consumption.

o  Mechanisms of organ damage.  Organ damage is the major medical
consequence of chronic alcohol abuse.  This damage is mostly to the
liver, brain, cardiovascular system, and pancreas.  Research is
needed into the underlying mechanisms of alcoholic hepatitis, brain
damage (especially alcohol dementia/Korsakoff's psychosis), portal
hypertension, cardiomyopathy, and pancreatitis.  Understanding these
mechanisms will lead to the development of medications that are
useful in alleviating or counteracting alcohol-induced tissue injury,
such as free radical scavengers, cognitive enhancers, and
transplantation.

Supported pharmacologic investigations should include use of
appropriate control groups, adequate sample sizes, and employment of
proper statistical analyses.  In evaluating the efficacy of all
pharmacologic agents, it is important to identify subtypes of
alcoholics particularly amenable to pharmacologic treatment as well
as to explore integration of pharmacotherapy with varying behavioral
and verbal therapies.  In addition, treatment interventions with
humans should be carefully described, and diagnostic and outcome
instruments should reflect state-of-the-art alcoholism assessment.
While developmental projects may employ highly homogeneous samples in
a single setting, it is desirable in later-stage research to include
greater heterogeneity in samples and sites.  Efficacy studies also
need to measure compliance with the pharmacologic intervention and
adequately verify self reports.  When possible, such studies should
assess overall safety and efficacy as well as identify effects
specific to major subtypes of subjects studied.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information should be included in the form PHS 398
in Sections 1-4 of the Research Plan AND summarized in Section 5,
Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to
be used in applying for these grants.  These forms are
available at most institutional offices of sponsored
research; from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 5333 Westbard
Avenue, Room 449, Bethesda, MD 20892, telephone 301/435-0714;
and from the NIAAA program administrators listed under INQUIRIES.

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the application.
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 2a of the face page of the application form and the YES box must
be marked.  Page limits and limits on size of type are strictly
enforced.  Applicants for FIRST Awards (R29) are reminded that such
applications must include three letters of reference.  Non-conforming
applications will be returned without being reviewed.

Applicants from institutions that have a General Clinical Research
Center (GCRC), funded by the NIH Division of Research Resources, may
wish to identify the Center as a resource for conducting the proposed
research.  If so, a letter of agreement from either the GCRC program
director or Principal Investigator should be included in the
application material.

The signed original, including the checklist, and three signed,
legible copies of the completed application must be sent to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Mark Green, Ph.D.
Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 409
Rockville, MD  20892
Telephone:  (301) 443-4375
FAX:  (301) 443-6077

Applications must be received by April 22, 1994.  If an application
is received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) 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.  The DRG will not accept
any application that is essentially the same as one already reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

The Division of Research Grants, NIH, serves as a central point for
receipt of applications for most discretionary PHS grant programs.
Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NIAAA.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NIAAA staff will contact
the applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.

Applications may be triaged by an NIAAA peer review group on the
basis of relative competitiveness.  The NIH will withdraw from
further competition those applications judged to be non-competitive
for award and notify the applicant Principal Investigator and
institutional official.  Those applications judged to be competitive
will undergo further scientific merit review.  Those applications
that are complete and responsive will be evaluated in accordance with
the criteria stated below for scientific/technical merit by an
appropriate peer review group convened by the NIAAA.  The second
level of review will be provided by the National Advisory Council on
Alcohol Abuse and Alcoholism.

Review Criteria

Criteria to be used in the scientific and technical merit review of
alcohol research grant applications will include the following:

1.  The scientific, technical, or medical significance and
originality of the proposed research.

2.  The appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research.

3.  The adequacy of the qualifications (including level of education
and training) and relevant research experience of the Principal
investigator and key research personnel.

4.  The availability of adequate facilities, general environment for
the conduct of the proposed research, other resources, and
collaborative arrangements necessary for the research.

5.  The reasonableness of budget estimates and duration for the
proposed research.

6.  Where applicable, the adequacy of procedures to protect or
minimize effects on animal and human subjects and the environment.

7.  Conformance of the application to the NIH policy on inclusion of
women and minorities in study populations.

The review criteria for FIRST Awards (R29) are contained in the FIRST
program announcement (revised September 1993).

AWARD CRITERIA

Applications recommended for approval by the National Advisory
Council on Alcohol Abuse and Alcoholism will be considered for
funding on the basis of the overall scientific and technical merit of
the application as determined by peer review, NIAAA programmatic
needs and balance, and the availability of funds.

INQUIRIES

Written and telephone inquiries concerning this FA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.  Potential applicants are encouraged to seek
preapplication
consultation in preparing an application under this RFA.

Direct inquiries regarding programmatic issues to:

Raye Z. Litten, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
5600 Fishers Lane, Room 14C-20
Rockville, MD  20857
Telephone:  (301) 443-0796
FAX:  (301) 443-8774

Direct inquiries regarding fiscal matters to:

Elsie Fleming
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
5600 Fishers Lane, Room 16-86
Rockville, MD  20857
Telephone:  (301) 443-4703
FAX:  (301) 443-3891

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.273.  Awards are made under the authorization of
the Public Health Service Act, Sections 301 and 464H, and
administered under the PHS grants policies and Federal Regulations at
Title 42 CFR Part 52, "Grants for Research Projects;" Title 45 CFR
Parts 74 and 92, "Administration of Grants;" and 45 CFR Part 46,
"Protections of Human Subjects."  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

.

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