DEVELOPMENT OF NOVEL DRUG AND GENE DELIVERY SYSTEMS AND DEVICES
RELEASE DATE: December 30, 2002
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
LETTER OF INTENT RECEIPT DATE: February 25, 2003
APPLICATION RECEIPT DATE: March 25, 2003
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:
PURPOSE OF THIS RFA
Although modern biotechnology has produced extremely sophisticated and
potent therapeutic drugs and genes, many of these compounds cannot be
effectively delivered using current drug and gene delivery techniques
(e.g., pills, injections, and viruses). The intent of this Request for
Applications (RFA) is to address the drug and gene delivery problem by
encouraging the submission of innovative research proposals, using
engineering principles and practice, to design, develop, and introduce
novel approaches, technologies, tools, and methods that will result in
new drug and gene delivery systems and devices. It is anticipated that
solving problems of drug and gene delivery will involve many scientific
fields, including pharmacology, biology, materials science, and
electrical, chemical, mechanical, and biomedical engineering and thus
teams of scientists and engineers are especially encouraged to apply.
Intricate with the development of new drugs and treatment modalities
should be the development of novel drug and gene delivery systems and
devices that are designed to overcome the current problems and
deficiencies associated with existing modes for systemic or localized
delivery of drugs and genes such as oral, intravenous, transdermal,
transmucosal, inhalation, in situ release via implants, and viral
vectors. It costs an estimated $150 million to create the average new
drug. Improving the effectiveness of an existing one by optimizing the
delivery and dosage, minimizing side effects, and finding new
therapeutic uses may be a better investment and more effective for
patients than creating a brand new drug.
The goal of this RFA is to encourage research to develop technologies
for targeted and controlled delivery of drugs, proteins, and genes with
reduced side effects and easier administration through the development
of novel delivery vehicles and devices that efficiently deliver
proteins, drugs and genes into cells.
To accomplish the goals of this initiative, multidisciplinary
collaborations among mechanical, electrical, chemical, and biomedical
engineers, materials scientists, and biologist and clinicians are highly
encouraged. The emphasis should be on an engineering approach, targeting
design goals and specifications with systematic and quantitative
analysis and prototyping, to transform drugs and/or genes into effective
therapies based on the method of delivery.
Topics that would be responsive to this RFA include, but are not
o Further development and improvement of delivery technologies such as
electroporation, iontophoresis, and ultrasound.
o Use of micromachining to design and develop small devices for novel
drug delivery applications such as micro- and nano-needle delivery
systems and micro-and nano-particles with controlled geometry for
clinically relevant delivery of drugs and genes.
o Development of new, non-conventional, delivery technologies and
devices that target drugs and genes to specific cell types in vivo.
o Development of implantable drug delivery devices that can reduce the
chance for both underdosing and overdosing, reduce the number of
necessary administrations, provide more localized and better use of
the active agents, and increase patient compliance.
o Engineering of new drug delivery profile systems that provide optimal
dosages of drugs precisely where and when they are needed and that
achieve and sustain complex delivery profiles.
o Development of new drug delivery matrix materials with designed or
on-demand drug release mechanisms, e.g. cell or receptor specific
triggering mechanisms versus hydrolytic degradation or erosion in
o Novel approaches to overcome the limitations of viral vectors, in
particular their relatively small capacity for therapeutic DNA,
safety concerns, and difficulty in targeting to specific cell types.
This should include the evaluation and development of alternative
vectors based on synthetic, non-viral systems or modifications of
o New concepts and strategies for drug delivery carriers integrating
targeted delivery with imaging capabilities. This may include the
development of activity-dependent probes, expression pattern probes,
molecular interaction probes, and single molecule reporters.
In all of the areas listed above, the NIBIB is interested in the
development of drug and gene delivery systems that could have broad
applications to biology and/or medicine while the NIDDK is interested
in applications to develop drug and gene delivery systems targeted at
diseases and/or organs within the mission of NIDDK
(http://www.niddk.nih.gov/welcome/mission.htm - mission), such as iron
chelating agents that are not orally-effective.
MECHANISM OF SUPPORT
This RFA will use the NIH research grant award mechanism (R01) and the
development/exploratory grant award mechanism (R21). As an applicant
you will be solely responsible for planning, directing, and executing
the proposed project. This RFA is a one-time solicitation. Future
unsolicited, competing-continuation R01 applications based on this
project will compete with all investigator-initiated applications and
will be reviewed according to the customary peer review procedures.
The anticipated award date is September 30, 2003.
The R01 mechanism is recommended for applications that emphasize basic
discovery or cross-cutting research that addresses specific aspects of
drug and gene delivery systems and devices. Research periods
associated with the R01 proposals are limited to five years with no cap
on budget amount.
The R21 Exploratory/Developmental Award supports exploratory or
developmental research aimed at proof-of-principle for high-risk
projects where very little or no preliminary data is available. An R21
application can be for up to two years with a maximum budget request of
$275,000 direct costs for the 2-year period and a maximum page limit of
15 pages. R21 applications are not renewable. Investigators are
encouraged to use data generated from the R21 application to apply for
further funding through the R01 mechanism (or other appropriate
This RFA uses just-in-time concepts. It also uses the modular as well
as the non-modular budgeting formats (see
Specifically, if you are submitting an application with direct costs
(including total costs of consortium arrangements) in each year of
$250,000 or less, use the modular format. Otherwise follow the
instructions for non-modular research grant applications.
The NIBIB intends to commit approximately $4,000,000, and the NIDDK
intends to commit approximately $350,000 in FY 2003 to fund 11 to 17
new and/or competitive continuation grants in response to this RFA. An
applicant may request a project period of up to 5 years for an R01 and
a project period of up to 2 years for an R21. Budgets for direct costs
of up to $275,000 for the 2-year period will be accepted for an R21.
There is no budget limitation for R01 applications.
Because the nature and scope of the proposed research will vary from
application to application, it is anticipated that the size and
duration of each award will also vary. Although the financial plans of
the NIBIB provide support for this program, awards pursuant to this RFA
are contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications.
You may submit (an) application(s) if your institution has any of the
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
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
carry out the proposed research is invited to work with their
institution to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH programs.
General Clinical Research Centers: 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.
Grantee Meetings: Principal Investigators will be required to attend
an annual meeting in the Bethesda, MD region organized by NIBIB.
Investigators must include travel to this meeting as part of the budget
request and state a willingness to participate in this meeting.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall into
two areas: scientific/research and financial or grants management
o Direct your questions about scientific/research issues to:
Peter Moy, Ph.D.
Division of Bioengineering
National Institute of Biomedical Imaging and Bioengineering
6707 Democracy Blvd.
Bethesda, MD 20892-5469
Telephone: (301) 496-9270
Fax: (301) 480-4973
Maren R. Laughlin, Ph.D.
Director, Metabolism Program
6707 Democracy Blvd, Rm. 6101, MSC 5460
Bethesda, MD 20892-5460
Telephone: (301) 594-8802
Fax: (301) 480-3503
o Direct your questions about financial or grants management matters
Ms. Pamela Mayer
Grants Management Branch
Division of Extramural Activities
National Institute of Biomedical Imaging and Bioengineering
6707 Democracy Blvd.
Bethesda, MD 20892
Telephone: (301) 451-4791
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that
includes the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review
workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning
of this document. The letter of intent should be sent to:
Meredith D. Temple, Ph.D.
Health Scientist Administrator
Division of Extramural Activities
National Institute of Biomedical Imaging and Bioengineering
6707 Democracy Blvd.
Bethesda, MD 20892
Telephone: (301) 451-4792
Fax: (301) 480-4973
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). The PHS 398 is
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications
requesting up to $250,000 per year in direct costs must be submitted in
a modular grant format. The modular grant format simplifies the
preparation of the budget in these applications by limiting the level
of budgetary detail. Applicants request direct costs in $25,000
modules. Section C of the research grant application instructions for
the PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants. Additional information
on modular grants is available at
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the face page
of the application. Type the RFA number on the label. 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 2 of the face
page of the application form and the YES box must be marked. The RFA
label is also available 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 received by the
application receipt date listed in the heading of this RFA. If an
application is received after that date, it will be returned to the
applicant without review.
The Center for Scientific Review (CSR) 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 CSR 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.
Please Note: As of November 27, 2001, all applications and other
deliveries to the Center for Scientific Review must come via courier
delivery or the USPS. Applications delivered by individuals to the
Center for Scientific Review will no longer be accepted. For
additional information, see the NIH Guide Notice
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the NIBIB. Incomplete applications will be
returned to the applicant without further consideration. And, if the
application is not responsive to the RFA, CSR staff may 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 appropriate NIH review cycle.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the CSR in accordance with the review criteria
stated below. As part of the initial merit review, all applications
o Receive a written critique
o Undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications
under review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory
council or board.
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
In the written comments, reviewers will be asked to discuss the
following aspects of your application in order to judge the likelihood
that the proposed research will have a substantial impact on the
pursuit of these goals:
The scientific review group will address and consider each of these
criteria in assigning your application's overall score, weighting them
as appropriate for each application. Your application does not need to
be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score. For example,
you may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.
(1) SIGNIFICANCE: Does your study address an important problem? If the
aims of your application are achieved, how do they advance scientific
knowledge? What will be the effect of these studies on the concepts or
methods that drive this field?
(2) APPROACH: Are the conceptual framework, design, methods, and
analyses adequately developed, well integrated, and appropriate to the
aims of the project? Do you acknowledge potential problem areas and
consider alternative tactics?
(3) INNOVATION: Does your project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does your project
challenge existing paradigms or develop new methodologies or
(4) INVESTIGATOR: Are you appropriately trained and well suited to
carry out this work? Is the work proposed appropriate to your
experience level as the principal investigator and to that of other
researchers (if any)?
(5) ENVIRONMENT: Does the scientific environment in which your work
will be done contribute to the probability of success? Do the proposed
experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there
evidence of institutional support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your
application will be reviewed with respect to the following:
o TEAM APPROACH: The inclusion of researchers with divergent
backgrounds, for example, the partnering of an engineer, a physiologist
and/or a clinician.
o R21 MECHANISM ONLY: Since the R21 mechanism is intended to encourage
exploratory/developmental research, proposals submitted as an R21 will
be reviewed based on their high risk/high impact potential and whether
or not the proposal is significantly distinct from those traditionally
submitted through the R01 mechanism. For example, R21 projects
designed to produce incremental advances in knowledge will not be
o PROTECTIONS: The adequacy of the proposed protection for humans,
animals, or the environment, to the extent they may be adversely
affected by the project proposed in the application.
o INCLUSION: The adequacy of plans to include subjects from both
genders, all racial and ethnic groups (and subgroups), and children as
appropriate for the scientific goals of the research. Plans for the
recruitment and retention of subjects will also be evaluated. (See
Inclusion Criteria included in the section on Federal Citations, below)
o BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: February 25, 2003
Application Receipt Date: March 25, 2003
Peer Review Date: May/June, 2003
Council Review: September, 2003
Earliest Anticipated Start Date: September 30, 2003
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy
of the NIH that women and members of minority groups and their sub-
populations must be included in all NIH-supported clinical research
projects unless a clear and compelling justification is provided
indicating that inclusion is inappropriate with respect to the health of
the subjects or the purpose of the research. This policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).
All investigators proposing clinical research should read the AMENDMENT
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research - Amended, October, 2001," published in the NIH Guide
for Grants and Contracts on October 9, 2001
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
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS: The NIH maintains a policy that children (i.e., individuals
under the age of 21) must be included in all human subjects research,
conducted or supported by the NIH, unless there are scientific and
ethical reasons not to include them. This policy applies to all initial
(Type 1) applications submitted for receipt dates after October 1,
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
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject
participants for all investigators submitting NIH proposals for research
involving human subjects. You will find this policy announcement in the
NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of
research on hESCs can be found at
http://grants.nih.gov/grants/stem_cells.htm and at
Only research using hESC lines that are registered in the NIH Human
Embryonic Stem Cell Registry will be eligible for Federal funding (see
http://escr.nih.gov). It is the responsibility of the applicant to
provide the official NIH identifier(s)for the hESC line(s)to be used in
the proposed research. Applications that do not provide this
information will be returned without review.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom of
Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at
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
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and
proposals for NIH funding must be self-contained within specified page
limitations. Unless otherwise specified in 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 site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting priority
areas. This RFA 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. 93.286 & 93.287 (NIBIB) and 93.847 &
93.849 (NIDDK) 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
http://grants.nih.gov/grants/policy/policy.htm and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products. In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a
facility) in which regular or routine education, library, day care,
health care, or early childhood development services are provided to
children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
Department of Health
and Human Services
National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892