Release Date: September 16, 1998

RFA:  DA-99-005


National Institute on Drug Abuse

Letter of Intent Receipt Date:  November 4, 1998
Application Receipt Date:  December 4, 1998


The purpose of this Request for Applications (RFA) is to solicit applications to
establish research centers called Medication Development Units (MDU) dedicated
to clinical research directed toward the identification, evaluation and
development of safe and effective pharmacotherapeutic treatments for cocaine,
methamphetamine, opiate, nicotine and cannabis abuse and addiction.  Research may
focus on currently approved or novel, investigational medications.

The treatment of cocaine, methamphetamine, opiate, nicotine or cannabis abuse and
addiction disorders necessitates a multidisciplinary approach.  Optimal
treatments may ultimately require a combined pharmacological and behavioral
treatment strategy.  Therefore, applications may propose the concurrent
evaluation of pharmacotherapy and behavioral treatments in an integrated design,
providing that such designs are of adequate size and are well controlled.

Applicants may focus on pilot Phase I safety/tolerability or Phase II or III
efficacy studies; human laboratory studies on medication interactions with other
drugs; pharmacokinetic or pharmacodynamic studies; or, if justified, multisite
efficacy studies.


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, Centers for the Development of
Medications to Treat Drug and Drug Addiction, is related to the priority areas
of tobacco, alcohol and other drugs, and HIV infection.  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


Applications may be submitted by domestic for-profit and non-profit
organizations, private and public, such as universities, colleges, hospitals,
laboratories, units of State and local governments, pharmaceutical companies, and
eligible agencies of the Federal government.  Racial/ethnic minority individuals,
women and persons with disabilities are encouraged to apply as Principal
Investigators.  Foreign institutions are not eligible.

Prospective investigators are encouraged to consult with the program official
listed under INQUIRIES for guidance on current NIDA priorities and how they apply
to the planned submission.


The National Institutes of Health (NIH) specialized research center grant (P50)
mechanism will be used under this RFA.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that of the

This RFA is a one time solicitation.  Any applications received after the single
receipt date will be returned to the applicant without further review.


It is anticipated that approximately $7.3 million in total costs will be
available to support the first year of funding.  This level of support is
dependent on the receipt of a sufficient number and diversity of applications of
high scientific merit.  It is anticipated that up to eight awards will be made. 
The total project period for an application submitted in response to this RFA may
not exceed 5 years.  The anticipated award date is August 1, 1999.

The size of individual awards will vary as a function of the nature and scope of
the research proposed.  However, awards are subject to a first year upper limit
of $1.0 million in total costs (direct plus indirect costs) and application
acceptability is contingent on this limit.  Exception to this budgetary
restriction can be made for multisite trials proposed to start in the first year
of the award and related to active trial conduct.  Budget requests should be
carefully justified and commensurate with the complexity of the project. 
Although this program is provided for in the financial plans of the NIDA, awards
pursuant to this RFA are contingent upon the availability of funds for this



Cocaine Abuse and Addiction.  Cocaine abuse and addiction has devastating
personal, social, and public health consequences.  National surveys indicate that
more than 2.2  million are current cocaine users.  Cocaine use is associated with
potentially life-threatening cardiovascular effects; sex-for-crack exchanges that
are spreading the AIDS virus among both drug-abusing and non-drug-abusing
populations; possible damage to infants born to women who abuse cocaine during
pregnancy; and violence and neighborhood disintegration related to the cocaine
marketplace.  To date, no medication has been approved for cocaine or other
stimulant abuse and addiction.

To address this critical deficiency, NIDA has made the development of an anti-
cocaine medication its number one priority.  This includes the development of
medications to treat a variety of aspects of cocaine abuse and addiction
including the short-term (< 3 months) abuse of cocaine, the long-term (>3 months)
relapse period intrinsic to cocaine addiction, as well as the  long-term
inhibition or reversal of neurotoxicity associated with persistent cocaine and/or
stimulant (e.g., methamphetamine) abuse and addiction.  This priority will also
influence funding decisions associated with grant applications.

Methamphetamine Abuse and Addiction.  Methamphetamine abuse and addiction is an
emerging public health problem largely confined to the western portion of the
United States.  Reflecting this increase is a doubling of emergency room
admissions for methamphetamine abuse between 1992 (300 admissions) and 1994 (733
admissions) and a doubling of admissions for treatment of addiction from 1993
(367 admissions) to 1995 (708 admissions) in Los Angeles County.

This RFA solicits research on medications to treat methamphetamine abuse and
addiction aimed at both its immediate and long-term consequences.  Immediate
consequences of abuse include serious medical presentations (e.g., convulsion and
cardiac arrhythmia) as well as psychiatric problems ranging from panic reactions
to psychosis.  Management of these problems is usually symptomatic.  Strategies
to reduce methamphetamine plasma concentrations could possibly serve as a useful
adjunct in the management of the acute medical and psychiatric symptomatology of
methamphetamine overdose.  Moreover, methamphetamine abuse and addiction have
been associated with cognitive, affective, and other psychiatric disturbances
(e.g., paranoia).  There are currently no pharmacotherapies for facilitation of
abstinence, relapse prevention, or agents that facilitate restoration of
cognitive abilities and reduce lingering paranoia.  Concerns about increased HIV
risk behaviors are well founded and may pertain especially to certain populations
(e.g., gay and bisexual men).  Thus, pharmacotherapies that reduce
methamphetamine use may reduce HIV risk behaviors and HIV transmission.

Opiate Abuse and Addiction.  Epidemiological trends suggest that the incidence
of heroin abuse and addiction has continued to increase since the 1980s.  Some
quite effective medications for therapeutic treatment of heroin addiction are
currently available.  However, these medications are not always appropriate for
some patients or under some circumstances.  Thus, three areas of opiate
pharmacotherapy are of interest to this RFA.  They include the use of non-opiate
medications for the long-term prevention of relapse, the short-term treatment of
symptoms (either acute or protracted) in medically assisted withdrawal and
research directed toward pharmacotherapy for dual addiction (opiate and stimulant
or opiate and alcohol).  Applications for opiate "substitution" pharmacotherapy
for opiate maintenance and medically assisted withdrawal approaches using
anesthetics are not of interest to this solicitation.

Nicotine Addiction.  The most preventable cause of premature mortality in
American society is cigarette smoking.  Nicotine is highly addictive and attempts
to quit cigarette smoking often end in failure.  The chewing of tobacco is also
addictive and may result in cancers of the mouth and throat.  The consequences
of abuse and addiction to tobacco are grave; over 400,000 premature deaths per
year are attributed to chronic smoking.  Moreover, chronic lung and cardiac
disorders are part of the morbidity associated with smoking.  Clearly,
pharmacotherapeutic agents which assist in smoking cessation would be a boon to
the public health.  To this end, NIDA is soliciting novel pharmacotherapeutic
approaches to smoking or tobacco chewing cessation.

Marijuana Addiction.  According to the Treatment Episode Data Set, treatment
admissions for marijuana/hashish addiction  have risen from 6.2% to 10.8% from
1992 to 1995, respectively.  Admissions for marijuana/hashish addiction make up
55% and 47% of the treatment admissions for the under 15 years old and 15-19 year
old age groups, respectively.  The current treatment of marijuana addiction is
a psychosocial-based approach.  NIDA is soliciting pharmacotherapeutic approaches
to assist marijuana-abusing individuals in eliminating their marijuana use.

RESEARCH THEMES.  The following are examples of research themes that such
Medication Development Units (MDUs) might utilize:

(1) Hypothesis driven research leading to Phase I or II medications studies.  For
example, systematic exploration of medications affecting stress-related hormones
of either the hypothalamic-pituitary-adrenal axis or the sympathetic-adrenal axis
and the therapeutic effects of these agents on drug abuse and addiction.  There
should be an integrated emphasis on one or two particular neurochemical
approaches -- for example modulation of a specific neurochemical system [e.g.,
dopamine (DA), norepinephrine (NE), serotonin (5-HT), glutamate and
neuromodulators associated with the glutamate cascade, cholecystokinin, opioid
peptides], specific mechanistic or receptor sites [e.g., DA, NE, 5-HT, glutamate
transporters or particular DA, NE, 5-HT, neuropeptide (including opioid)

(2) Special populations research defining the influence of medications on a
specific group of individuals.  For example, studies on the efficacy of
medications on individuals with a co-morbid drug abuse disorder (e.g., cocaine
and alcohol abuse and addiction), a co-morbid psychiatric disorder (depression,
attention deficit disorder, schizophrenia), or other ?subject? factors including
the influence of sex, age, or biological/brain markers serving as possible
predictors of the efficacy of a medication.  For brain imaging, a variety of
modalities may be used to define such predictors (e.g., positron emission
tomography (PET), simplified dual probe detector PET, functional magnetic
resonance imaging).  Note: Investigators emphasizing the special populations
theme in their MDU should demonstrate their capacity to assess subjects in these
categories in sufficient numbers for a 2-3 year period per therapeutic project.

(3) Research directed toward the improvement of the quality of clinical trials. 
This includes the assessment of methods designed to enhance the sensitivity of
clinical trials to detect treatment differences over the placebo.


An MDU grant is awarded to an institution on behalf of an MDU Director for the
support of a broadly based, long term research and development program with a
particular major objective or theme.  Award duration will not exceed 5 years. 
The philosophy of MDU center grant application (P50) review requires that each
scientific project be assessed within the context of the entire program. 
Therefore, each application must conform to the following requirements:

The MDU and its components must have demonstrated capability to conduct full
scale single site clinical trials (placebo-controlled (PC) or active controlled
(AC), double-blind (DB)) using the proposed therapeutic approach.  Applicants
opting to propose multisite trials must have adequately demonstrated efficacy in
a single site PC/AC, DB trial.  Such applicants must also demonstrate the ability
to affiliate rapidly with other sites (through subcontract or collaborative
mechanisms) to launch a multi-site Phase II or Phase III PC/AC, DB trial.

The MDU Director must possess recognized scientific and administrative
competence.  The Center Director must show a substantial commitment of time and
effort (minimum 25%) to the program and exercise leadership in steering the MDU
direction and maintenance of its quality control.  Management functions may be
accomplished through an administrative core.

The MDU provides for administrative and scientific core components such as
project management, clinical resources, laboratory equipment and support,
statistical support, etc., which are shared by more than one project.

An administrative Core provides for central operations, technical support and
exercise of leadership for the overall project management, integration,
communication and coordination of the MDU.

GCP compliance. Each research project, depending on the nature of the program,
should also contain documents of GCP (Good Clinical Practice) including assurance
of regulatory compliance with respect to submissions of medications protocols to
the IRB and to the FDA.

5.  The integration of the proposed work should be clearly demonstrated and lead
to original and creative contributions related to the objective or theme over and
above those which would be obtained if each component of the MDU existed


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 biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided 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 research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research", which were published in the Federal Register of March 28, 1994 (FR 59
14508-14513), and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994.  Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also provide
additional relevant information concerning the policy.


It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted and 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 was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:


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 before submitting an application that
involves the administration of compounds to human subjects.  The guidelines are
available on the NIDA Home Page at or may
be obtained by calling (301) 443-2755.


Prospective applicants are asked to submit, by November 4, 1998, a letter of
intent that includes a descriptive title of the overall proposed research; the
name, address, telephone number, and institution of the Principal Investigator; 
title of each major project, names of investigators, and their respective
institutions; and the number and title of the RFA in response to which the
application may be submitted.

The letter of intent from the investigator is not binding, nor is it a factor in
the peer review of the application.  The information they contain is helpful in
planning for the review of applications.

The letter of intent is to be sent to:

Office of Extramural Program Review
National Institute on Drug Abuse
5600 Fishers Lane, Room 10-42
Rockville, MD  20857
Telephone:  (301) 443-2755


Applications are to be submitted on the research grant application form PHS 398
(rev. 5/95).  These forms are available at most institutional offices of
sponsored research and may also be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910; telephone 301-435-0714, Email:

Applications must conform to the SPECIAL REQUIREMENTS described above.  Because
of the multi-project nature of a Medications Development Unit grant and the
special requirements in this RFA, additional instructions regarding format are

Applicants are encouraged to organize their application by initially presenting
the face page, the abstract page with key personnel, a table of contents, summary
budget pages for the entire MDU, and other documentation pertaining to the entire
MDU.  This should be followed by an Introductory Section of no more than three
pages.  It should be written for the proposed MDU application describing it as
a whole with respect to the overall theme, goals, objectives, and overall
research plan.  The Introductory Section should contain information on i) the
overall research theme, ii) timelines and milestones for each projects in a
graphic outline to clearly lay out the sequence of research events and how each
project of the MDU relates to each other, iii) the capacity of the MDU to conduct
adequately sized clinical trials for the targeted indications within a time frame
of 2-3 years per project, and  iv) the capability of the proposed Principal
Investigator and his/her institution to carry out the scientific and
administrative duties required in this RFA.

After the introductory section, each core and research project should be
presented with its accompanying individual budget, budget justification,
biographical sketches, and other support information and research plan.  For each
core and research project component, there is a 25 page limit for the sections
of the research plan (i.e., specific aims, background and significance,
preliminary studies/progress report, and research design and methods) as
indicated in the form PHS 398.  Appendix material limits apply to each component
separately; each component's appendix may include up to 10 publications,
manuscripts, abstracts, patents, or other printed material directly related to
the project.  Surveys, questionnaires, data collection instruments, and clinical
protocols may also be submitted in the appendix.  Original glossy photographs or
color images may be included, provided that a photocopy (that may be reduced in
size) is included within the 25 pages of the research plan.  Applications
exceeding page limits, font limits, or appendix limits will be returned to the
applicant without review.  Appendices should not be placed within the body of the
application  when submitting, but should be bundled separately, component by

The RFA label available in the PHS 398 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, to ensure the identification
of the application with this RFA the "YES" box must be marked in item 2 of the
face page of the application form and the title and number of this RFA typed. 
Applications that are not received as a single package from the Principal
Investigator and that do not conform to the instructions contained in PHS 398
(rev. 5/95) application kit will be judged non-responsive and will be returned
to the applicant.

The completed original, including the checklist, and three legible copies must
be sent or delivered to:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC-7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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

Office of Extramural Program Review
National Institute on Drug Abuse
5600 Fishers Lane, Room 10-42
Rockville, MD  20857
Telephone:  (301) 443-2755

Applications must be received by December 4, 1998.  If an application is received
after this date, it will be returned to the applicant without review.  If the
application submitted in response to this RFA is substantially similar to a grant
application already submitted to the NIH for review, the applicant will be asked
to withdraw either the pending application or the new one.  Simultaneous
submission of identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.


A.  Review procedures

Applications will be reviewed by the Center for Scientific Review (CSR) for
completeness and by NIDA staff to determine programmatic responsiveness to this
RFA.  Applications deemed to be non-responsive will be returned to the applicant
without review.  An application with first year total costs (direct and indirect)
in excess of $1.0 million will be returned without review, except for those that
include active multisite trials in the first year.

An appropriate NIDA peer review group convened in accordance with NIH peer review
procedures will evaluate applications that are complete and responsive to the RFA
for scientific and technical merit.  As part of the initial merit review, all
applications will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit, generally the top
half of applications under review, will be discussed, assigned priority score,
and receive a second level review by the National Advisory Council on Drug Abuse.

The review group will review the MDU application as an integrated research effort
focused on a central research theme.  The review group will assess the scientific
and technical merit of the proposal according to the following criteria and
assign one overall priority score for the entire MDU application.  In addition,
each application must meet the Special Requirements identified above.  When
appropriate, these requirements will also serve as review criteria.

B.  Review Criteria

Scientific Review Group (SRG) review of the scientific and technical merit of MDU
grant application will emphasize review of the program as an integrated research
effort focused on a medications development theme.  The review will also include
an assessment of the academic climate and physical environment and special
considerations, e.g., compliance with the human subjects and animal welfare
regulations.  The assessment of the scientific and technical merit will include
the following:

Significance of the application's impact on pharmacotherapeutic issues in drug
addiction treatment and significance of the overall program goals and the
development of a well-defined research and development focus of importance and
relevance to the goals of this RFA.  The application should focus on the timely
development of a database of clinical information that will support the
advancement of a given pharmacotherapy toward advanced efficacy trials that would
themselves support New Drug Applications. Approach:  Are the conceptual
framework, design, methods, and analyses adequately developed, well integrated,
and appropriate to the aims of the project?

Medication testing and development plan:  Clarity of overall medications
development research theme supported by a strong rationale;  timelines and
milestones for each projects in a graphic outline (Gantt and/or Pert charts) is
suggested to clearly lay out the sequence of research events and how each project
of the MDU relates to each other;  and criteria for go/no go decisions at
critical points in plan.  Plan must indicate that therapeutic trials will be
initiated within 6 months of the award date and the results of a particular trial
will be completed and analyzed in 2-3 years.

Adequacy and feasibility of approach:  In view of the overall objectives, is the
proposed approach reasonable?  Is it likely to be carried out and completed
without any major complications or hindrances?  Does the applicant recognize and
present solutions for potential problems which might arise?

The justification for, and usefulness of core facilities (if any) to the research
projects:  Core unit(s) provide essential facilities or services for the
individual projects, including administrative arrangements and organization to
facilitate and monitor the attainment of objectives and quality control.  For
example, these factors will include plans to enhance communication and
cooperation among the investigators involved in the program and mechanisms for
the allocations of funds for day-to-day management, project management and
tracking, contractual agreements and procedures for the replacement of key
personnel, such as the Principal Investigators, if required on an interim or
permanent basis.

Assurance of compound accessibility:  The proposal, depending on the nature of
the program, must have assurance of the accessibility and availability of the
proposed test compounds.  A prerequisite for consideration of any study within
an application is the demonstrated access to the study compounds as well as
necessary formulations as required.  This includes necessary placebo forms of the
test drug formulation.

Assurance of Accessibility to Patient Population and Controls:  Each project
involving human subjects,  depending on the nature of the program, must
demonstrate the ability to acquire the specified patients at a rate sufficient
to meet the sample size within the 2-3 years study duration, or there must be
clear demonstration of target population availability and means to recruit
successfully must be provided.

Data Management and Statistical Resource:  Each project should propose the plan
for data management and demonstrate appropriate statistical resources to manage,
analyze clinical data and draft summary reports to support IND and possible NDA
submissions.  Is the general approach to data reduction and analysis clearly

G.  Integration:  The integration of the proposed work should be clearly
demonstrated and lead to original and creative contributions related to the
objective or theme over and above those which would be obtained if each component
of the MDU existed independently.

H.  For applications that include multisite trials:  in addition to
appropriateness of proposed methodology and statistical analyses, demonstrate a
willingness to work as part of a clinical trials network and use standard
methodology and instrumentation as core measures as well as a specific behavioral
platform that may be in common or parallel to that used by the Medications
Development Division, NIDA.  Such trials must also demonstrate well coordinated
management plans for subcontracting multisites or coordinating collaborative
arrangements.  These collaborations cannot be proposed as projects on more than
one competing MDU applications to this RFA.

Innovation:  Does the project employ novel concepts, approaches or method? Are
the aims original and innovative?  Does the project challenge existing paradigms
or develop new methodologies or technologies?

Investigators:  The scientific leadership, ability, stature, experience, and
administrative competence of the Project Director and his or her commitment and
ability to devote substantial time and effort (at least 25%) to the program.  The
scientific stature of the Principal Investigators on the research projects and
core components and the extent to which each PI contributes to the overall
program goals as well as their commitment to the program.

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?  Are
test compounds available and are formulations appropriate?

Budget:  The appropriateness and Reasonableness of the overall budget for the
proposed work.  Are all items well justified in terms of the aims of the MDU,
particularly major and expensive items of equipment, costly supplies and
personnel, etc.

6.  Adequacy of plans to protect human subjects, animal subjects, and the
environment, as appropriate, and adequacy of plans for the inclusion of both
genders, minority groups, and children, as appropriate to the goals of the


Applications recommended for further consideration by the National Advisory
Council on Drug Abuse will be considered for funding based on the following

1.  Overall scientific and technical merit of the proposal as determined by peer
2.  Program priorities (which include cocaine abuse and addiction therapy as the
first priority).
3.  Availability of funds.


Letter of Intent Receipt Date:  November 4, 1998
Application Receipt Date:       December 4, 1998
Scientific Review Date:         March 1999
Council Meeting Date:           May 1999
Earliest Award Date:            August 1999


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applications is welcome.  Direct inquiries
regarding programmatic issues to:

Richard Hawks, Ph.D.
Medications Development Division
National Institute on Drug Abuse
5600 Fishers Lane, Room 11A-55
Rockville, MD  20857
Telephone:  (301) 443-3318/9799
FAX:  (301) 443-2599

Direct inquiries regarding fiscal matters to:

Gary Fleming, J.D., M.S.
Grants Management Branch
National Institute on Drug Abuse
5600 Fishers Lane, Room 8A-54
Rockville, MD  20857
Telephone:  (301) 443-6710


This program is described in the Catalog of Federal Domestic Assistance No.
93.279.  Awards are made under the authority of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241
and 285) and administered under PHS grant policies and Federal Regulations 42 CFR
Part 52 and 45 CFR Parts 74 and 92.  This program is not subject to the
intergovernmental review requirements of Executive Order 122372 or Health Systems
Agency Review.

The Public Health Service strongly encourages all grant recipients to provide a
smoke-free workplace and promote the non-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

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