NOVEL DRUG DELIVERY SYSTEMS FOR TREATMENT OF DRUG ABUSE

NIH GUIDE, Volume 21, Number 39, October 30, 1992



PA:  PA-93-012



P.T.





Keywords:



National Institute on Drug Abuse



THE PROGRAM ANNOUNCEMENT (PA) ANNOUNCED IN THIS NOTICE CONTAINS

ESSENTIAL INFORMATION FOR THE PREPARATION OF AN APPLICATION.

POTENTIAL APPLICANTS MAY OBTAIN THE PA FROM THE CONTACT NAMED IN

INQUIRIES, BELOW.



PURPOSE



The purpose of this announcement is to stimulate research directed at

the design and development of pharmaceutical dosage forms/drug

delivery systems to improve the efficacy of pharmacotherapeutic

agents for the treatment of drug abuse.  The development of

pharmaceutical formulations for the treatment of withdrawal symptoms

of neonates/infants born to drug-dependent mothers is also included.



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, for-profit and

non-profit organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal government.

Applications from minority individuals and women are encouraged.

Foreign applicants are not eligible for First Independent Research

Support and Transition (FIRST) (R29) awards.



MECHANISMS OF SUPPORT



Support mechanisms include Research Program Project (P01), Research

Projects (R01), Small Grants (R03), and FIRST (R29) awards.  Most

investigator-initiated research is supported by research project

grants (R01).  Research grants are awarded to institutions on behalf

of Principal Investigators who have designed and will direct a

specific project or set of projects.  For information on the special

requirements of the FIRST (R29) awards and small grants (R03),

contact the program staff listed at the end of this announcement.



RESEARCH OBJECTIVES



Specific areas of interest include, but are not limited to, the

following:



Information on pharmacokinetics and pharmacodynamics of a drug is

essential for the understanding of concentration-effect relationships

and thus provides a basis for the rational design of optimum drug

delivery systems.  Therefore, studies specifically designed to

characterize pharmacokinetics and pharmacodynamics relevant to drug

delivery system development are encouraged.  The development of novel

assay methods for the quantification of drug concentrations in the

biological systems to facilitate such pharmacokinetic/pharmacodynamic

studies is also solicited.  In addition, research directed at the

investigation of tolerance development pertinent to the design of

delivery systems for opiate agonist and partial agonist types of

treatment drugs is also encouraged, as tolerance often develops

rapidly under conditions of constant blood concentrations.



Controlled-release delivery systems that provide optimum drug effects

by controlling the absorption rate and duration in the systemic

circulation will be very useful for drug abuse treatment.  Of

interest is research directed at the investigation of mechanisms and

factors (biological and physicochemical) that govern and affect the

release rates as well as the drug absorption rates.  Investigations

of innovative methodology and technology based on a sound mechanistic

and biological approach for the development of controlled-release

drug delivery systems are encouraged.  Studies are also solicited for

the search for biologically relevant in vitro models or methodologies

for the evaluation of these drug delivery systems.



Of particular interest among the controlled-release systems are

sustained-release systems that will provide effective concentrations

for a long period of time.  Such systems reduce dosing frequency, and

thus, not only improve treatment compliance, but also reduce the

necessity for frequent clinic visits.  The development of parenteral

depot systems that could provide drug effects from one to two weeks

is especially encouraged, since such systems also eliminate diversion

problems associated with take-home doses.  Transdermal systems and

other systems to provide prolonged drug effects are also of interest,

if the possibility of diversion could be minimized or eliminated.



Convenience of the dose administration is important in treatment

clinics, particularly in view of the need to observe dosing to ensure

compliance.  The oral route is the most convenient means for

administration.  However, the duration of orally administrated drugs

is limited by the gastrointestinal retention time.  Research directed

at the development of technology to prolong the retention of

medications in the gastrointestinal tract for more than 1 day is also

encouraged.



Approaches for the design of pharmaceutical products that improve the

bioavailability of drugs with high first-pass metabolism or

significant gastrointestinal degradation are of interest.  Design of

innovative dosage forms to protect the drug from chemical or

enzymatic degradation in the gastrointestinal tract is encouraged.

Mechanistic investigations of alternate routes of administration to

bypass the gastrointestinal tract, such as sublingual/buccal, rectal,

and transdermal routes, are solicited.



A triggered-release system which would release the

pharmacotherapeutic agent only when patients take abused drugs or

when patients need it could be extremely advantageous. Applications

are requested concerning an immunologically based delivery system

that utilizes antigen-antibody interactions to "trigger" the system

for the release of the pharmacotherapeutic agents.



Research is solicited for the development of strategies to overcome

the diversion problem associated with maintenance drugs.  Included

are approaches for new design of pharmaceutical dosage forms such

that the extraction of the active ingredient for intravenous use is

prevented.  Studies are also encouraged for the design of

formulations that deter the diversion by incorporating an antagonist

in such a manner that the antagonist, by design, via physicochemical

or pharmacokinetic properties, is not bioavailable with the intended

route of administration, but is bioavailable with the unintended

intravenous route of administration and will, as a consequence,

precipitate withdrawal.



Other novel approaches for the development of drug delivery systems

with potential clinical relevance for the treatment of drug abuse

will also be encouraged.



In these applications for grant funding, programmatic emphasis will

be placed on innovation in design and development.  To qualify for

this funding program, applications should embody unique and/or

innovative theoretical constructs with an experimental approach

leading to a new system of drug delivery or administration or be

uniquely suited to a particular pharmacotherapy in the drug abuse

area.



NIH POLICY CONCERNING INCLUSION OF MINORITIES AND WOMEN AS SUBJECTS

IN RESEARCH



Applications for grants and cooperative agreements and proposals for

contracts that involve human subjects are required to include

minorities and both genders 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 applies to all research involving human subjects

and human materials, and applies to males and females of all ages.

If one gender and/or minorities are excluded or are inadequately

represented in this research, particularly in proposed

population-based studies, a clear compelling rationale for exclusion

or inadequate representation should be provided.  The composition of

the proposed study population must be described in terms of gender

and racial/ethnic group, together with a rationale for its choice.

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.



Applicants are urged to assess carefully the feasibility of including

the broadest possible representation of minority groups.  However,

the 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., American

Indians or Alaskan Natives, Asians or Pacific Islanders, Blacks,

Hispanics).  Investigators must provide the rationale for studies on

single minority population groups.



Applications for support of research involving human subjects must

employ a study design with minority and/or gender representation (by

age distribution, risk factors, incidence/prevalence, etc.,)

appropriate to the scientific objectives of the research.  It is not

an automatic requirement for the study design to provide statistical

power to answer the questions posed for men and women and

racial/ethnic groups separately; however, whenever there are

scientific reasons to anticipate differences between men and women,

and racial/ethnic groups, with regard to the hypothesis under

investigation, applicants should include an evaluation of these

gender and minority group differences in the proposed study.  If

adequate inclusion of one gender and/or minorities is impossible or

inappropriate with respect to the purpose of the research, because of

the health of the subjects, or other reasons, or if in the only study

population available, there is a disproportionate representation of

one gender or minority/majority group, the rationale for the study

population must be well explained and justified.



The NIH funding components will not make awards of grants,

cooperative agreements or contracts that do not comply with this

policy.  For research awards which are covered by this policy,

awardees will report annually on enrollment of women and men, and on

the race and ethnicity of subjects.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application from PHS

398 (rev. 9/91) and will be accepted at the standard application

deadlines as indicated in the application kit.  The receipt dates for

applications for AIDS-related research are found in the PHS 398

instructions.



Application kits containing the necessary forms and instructions may

be obtained from the business office or office of sponsored research

at most universities, colleges, medical schools, and other major

research facilities.  If not available from these sources, the

information may be obtained from the Office of Grants Inquiries,

Division of Research Grants, National Institutes of Health, Westwood

Building, Room 240, 5333 Westbard Avenue, Bethesda, MD 20892,

telephone (301) 496-7441.  The title and number of the announcement

must be typed in Section 2a on the face page of the application.



The completed original application and five legible copies must be

sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center for Research

Resources may wish to identify the GCRC 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

with the application.



REVIEW CONSIDERATIONS



The Division of Research Grants, NIH, serves as a central point for

receipt of applications.  Applications received under this

announcement will be assigned to an initial review group (IRG) for

scientific review in accordance with established Public Health

Service Referral Guidelines.  The IRGs consist primarily of non-

Federal experts.  Notification of the review outcome will be sent to

the applicant after the initial review.



Applications will receive a secondary review for policy

considerations by the appropriate National Advisory Council.  Only

applications recommended for further consideration by Council may be

considered for funding.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications assigned to the Institute.  Applications recommended for

further consideration by the appropriate National Advisory Council

will be considered for funding on the basis of overall scientific and

technical merit of the application as determined by peer review,

Institute program needs and balance, and availability of funds.



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding programmatic issues and requests for the

Program Announcement to:



C. Nora Chiang, Ph.D.

Chemistry and Pharmaceutics Branch

National Institute on Drug Abuse

5600 Fishers Lane, Room 11A55

Rockville, MD  20857

Telephone:  (301) 443-5280



Direct inquiries regarding fiscal matters to:



Shirley Denney

Office of Planning and Resource Management

National Institute on Drug Abuse

5600 Fishers Lane, Room 8A-54

Rockville, MD  20857

Telephone:  (301) 443-6710



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance No. 93.279.  Awards are made under the authorization of

the Public Health Service Act, sections 301 and 515 (42 U.S.C 241 and

290cc) and administered under PHS grants policies and Federal

Regulations 42 CFR 92 and 45 CFR Part 74.  This program is not

subject to the intergovernmental review requirements of Executive

Order 12372 as implemented under Department of Health and Human

Services regulations at 45 CFR Part 100 or Health Systems Agency

review.  Special attention is called to 42 CFR Part 2,

Confidentiality of Alcohol and Drug Abuse Patient Records.



.

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