ALZHEIMER'S DISEASE CLINICAL TRIAL PLANNING GRANT

Release Date:  January 14, 1999

PA NUMBER:  PA-99-039

P.T.

National Institute on Aging
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke

PURPOSE

The National Institute on Aging (NIA), the National Institute of Mental Health
(NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS)
invite qualified investigators to submit research grant applications for clinical
trial planning grants directed toward the drug treatment of the cognitive and
behavioral symptoms of Alzheimer's Disease (AD).  The purpose of the Alzheimer's
Disease Clinical Trial Planning Grant is to allow for early peer review of the
rationale and design for Alzheimer's disease clinical drug trials and to provide
support for the development of a detailed clinical trial research plan, including
a manual of operations and procedures.

Note:  There is a companion Program Announcement available for "Alzheimer's
Disease Pilot Clinical Trials" (PA-99-038).

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 PA, ALZHEIMER'S DISEASE CLINICAL TRIAL
PLANNING GRANT, is related to the priority area of chronic disabling conditions. 
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 202-512-1800) or at
http://www.crisny.org/health/us/health7.html.

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. Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

The mechanism of support for the Alzheimer's Disease Clinical Trial Planning
Grant is the Developmental Planning Grant (R21), which will provide up to
$150,000 in direct costs for a single year.  The award cannot be renewed.

RESEARCH OBJECTIVES

I. BACKGROUND

Alzheimer's disease (AD) is one of the most persistent and devastating dementing
disorders of old age, because it eventually leads to a complete loss of memory
and of the ability to function independently.  It is estimated that up to four
million people in the United States have AD in its various stages at an estimated
cost to society of $90 billion per year, and it is projected that 14 million
people could be victims of Alzheimer's disease by the middle of the next century. 
The disease presents enormous problems not only to affected individuals but also
to their families and raises many complex social and economic issues for the
country.

AD provides a complex neurobiological puzzle. Its etiology is not known, and the
pathobiological processes that underlie the steady progression of the clinical
course of this disease are not yet completely understood.  It is clear, however,
that mechanisms of cell to cell communication are disrupted.  These involve
several different types of neurotransmitter, neuropeptide, and neuromodulator
systems, neurochemical processes, protein trafficking, and elements of oxidative
and cellular energy metabolism processes.  The hallmark of the disease involves
progressive cell dysfunction, cell loss, and the accumulation of a variety of
abnormal protein and cytoskeletal abnormalities.  It is still not known when and
how the degenerative process begins.

At present there are no generally safe and effective treatments for the cognitive
and behavioral symptoms of AD. The few agents that are currently approved by the
Food and Drug Administration have demonstrated only modest effects in modifying
the disease symptoms for relatively short periods in subsets of patients, and
none has shown an effect on disease progression.  The majority of the compounds
considered candidate drugs have generally been designed to affect the synthesis,
release, or degradation of neurotransmitters.  Most of the agents available thus
far have been targeted towards the cholinergic system which is an especially
vulnerable neural population in AD and cognitive function.

The NIA, NIMH, NINDS and other NIH Institutes currently support extramural and
intramural projects for the study of the epidemiology, etiology, diagnosis, and
treatment of AD.  Notwithstanding these efforts, the increasing numbers of
affected individuals, the unknown etiology, the emotional, social, and economic
costs to the victims, caregivers, and society, and the fact that there is no
compound which can uniformly slow or reverse the progression of the disease or
ameliorate the cognitive and behavioral symptoms, all require that the most
creative scientific talents be mobilized to aggressively pursue a concerted
effort to discover and test new treatments for Alzheimer's disease.  Although
agents are still needed which can reliably ameliorate the cognitive and
behavioral symptoms of the disease even for a short time (because such agents
would provide needed relief, however brief, to the victims and their families),
more efforts need to be focused on testing interventions which could potentially
slow the disease progression, reverse the disease process, and delay the onset
of or prevent AD entirely.

II. RESEARCH OBJECTIVES AND SCOPE

The objective of this solicitation is to provide support for the extensive
efforts required to develop a detailed clinical trial protocol and to organize
an effective group of investigators.  After the basic design and rationale for
an Alzheimer's disease drug intervention trial have been determined, the
Alzheimer's Disease Clinical Trial Planning Grant will support the development
of the specific aspects of the trial which will be essential to the conduct of
a successful full-scale clinical trial.  This includes adequate plans for the
following: recruitment and retention of patients; experimental design and
protocols; data management; analytical techniques; facilities; administrative
procedures; and collaborative arrangements.

Detailed information regarding the rationale of the clinical trial, based on
adequate preclinical data and preliminary clinical research, must be developed
prior to submission and included in the application for an Alzheimer's Disease
Clinical Trial Planning Grant.  The purpose of the planning grant is not to
obtain preliminary data or to conduct studies to support the rationale for the
clinical trial.  The expected product of the planning grant is a detailed
clinical trial research plan including a manual of operations and procedures.

SPECIFIC REQUIREMENTS TO BE ADDRESSED IN THE APPLICATION

1.  Rationale. The background and significance of the application must address
the rationale for a future, full-scale, randomized clinical trial (RCT)
including:
- reasons for selection of intervention and mode of delivery including specific
details such as dose or a particular procedure;
- the biological mechanisms and clinical data that support conducting an RCT;
- information adequate to determine the significance and need to perform an RCT;
- compelling need to proceed with an RCT as soon as possible (e.g. impact on
health care);
- competitive therapies--advantages and disadvantages;
- ethical issues surrounding an RCT;
- a clear statement of the question that an RCT would address.

2.  Experimental Design. The application for a planning grant should include a
full description of the experimental design of the future RCT, including:
- translation of the clinical question into a statistical hypothesis;
- sample size and duration of the RCT;
- endpoint(s), outcome measures, and data to be collected;
- randomization, masking, and inclusion/exclusion criteria;
- the strengths and weaknesses of the proposed methods, and possible
alternatives;
- ancillary therapies;
- capability to develop methods for standardization of procedures for data
management and quality control.

3.  Plans to Address Patient Recruitment/Retention.  The application must address
the following items:
- plans for documenting the availability of the requisite eligible patient pool;
- plans for including women and minority individuals as trial participants and
plans for recruitment outreach, as appropriate;
- follow-up procedures to ensure adherence to protocols, retention of subjects,
and collection of data at stated intervals.

4.  Investigators. The application must include a clear statement of the
leadership and proposed organization of the RCT, including:
- identification of a principal investigator, and, for multi-center trials,
identification of study investigators at each of the sites;
- professional training and experience of the trial organizers in such areas as
the clinical problem under study, administration of complex projects, and study
design;
- inclusion of statisticians, data managers and study coordinators;
- use of study monitors in multi-site studies;
- plans to add or drop centers;
- essential committee structure, i.e., Planning, Steering, Executive,
Publication, Data and Safety Monitoring.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations 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 have been 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 available on the web at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not94-105.html

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may provide additional information concerning the
policy.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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 or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

NOTE FOR APPLICATIONS FOCUSED ON AGING RESEARCH

Applications received in response to this program announcement are expected to
focus on scientific issues related to aging and to aging-related aspects of
disease. In describing the plan to recruit human subjects, investigators may cite
a focus on aging or on aging-related aspects of disease as the justification for
why children will be excluded. In this regard applicants may use Justification
1, the research topic to be studied is irrelevant to children, from the policy
announcement.

NIA REQUIREMENTS FOR HUMAN INTERVENTION STUDIES

NIA has specific requirements for human intervention studies that need to be
addressed in the grant application.  These requirements are directed toward
protecting the safety of participants in intervention studies and assuring that
trials are soundly conducted and analyzed.  These requirements, "Implementation
of Policies for Human Intervention Studies," have been published in the NIH Guide
for Grants and Contracts, Vol. 25, No. 33, October 4, 1996; available at:
http://www.nih.gov/grants/guide/notice-files/not96-237.html.  In
addition, NIH has recently indicated the NIH policy concerned with data and
safety monitoring in the NIH Guide for Grants and Contracts for the week of June
12, 1998.  The title is "NIH Policy for Data and Safety Monitoring," and the URL
address is http://www.nih.gov/grants/guide/notice-files/not98-084.html.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated in
the application kit. Applications kits are available at most institutional
offices of sponsored research and may 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:
GrantsInfo@nih.gov.  Applications are also available on the World Wide Web at
http://www.nih.gov/grants/funding/phs398/phs398.html.

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

Submit the signed, original, single-sided application along with four exact,
single-sided copies and four collated sets of appendix materials 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)

In order to facilitate the review of applications, at the same time, mail or
deliver one copy of the application to:

Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C212, MSC 9205
Bethesda, MD  20892-9205
Email:  Mary_Nekola@nih.gov

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer review group convened in accordance with
the standard NIH peer review procedures.  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 a priority
score, and receive a second level review by the appropriate national advisory
council or board.

Review Criteria

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 the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

Significance: Does this study address an important problem? If the aims of the
application are achieved, how will scientific knowledge be advanced? What will
be the effect of these studies on the concepts or methods that drive this field?

Approach: Are the conceptual framework, design, methods, and analyses adequately
developed, well-integrated, and appropriate to the aims of the project? Does the
applicant acknowledge potential problem areas and consider alternative tactics?

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

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

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

In addition, the "Specific Requirements To Be Addressed In The Application" will
be evaluated, and the adequacy of plans to include both genders and minorities
and their subgroups as appropriate for the scientific goals of the research will
be reviewed.  Plans for the recruitment and retention of subjects will also be
evaluated.

The initial review group will also examine the provisions for the protection of
human subjects, the safety of the research environment, and conformance with the
NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical
Research and the NIA Guidelines for the Implementation of Policies for Human
Intervention Studies.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications. The following will be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Program priority

INQUIRIES

Inquiries are encouraged. The opportunity to clarify any issues or questions from
potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Neil S. Buckholtz, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  Buckholn@exmur.nia.nih.gov

Eugene J. Oliver, Ph.D.
Division of Stroke, Trauma, and Neurodegenerative Disorders
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 806
Bethesda, MD  20892
Telephone:  (301) 496-5680
FAX:  (301) 480-1080
Email:  eollc@nih.gov

George T. Niederehe, Ph.D.
National Institute of  Mental Health
5600 Fishers Lane, Room 10-75
Rockville, MD  20857
Telephone:  (301) 443-1185
FAX:  (301) 594-6784
Email:  gniedere@mail.nih.gov

Direct inquiries regarding fiscal matters to:

Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email: Joseph_Ellis@nih.gov

Pat Driscoll
Grants Management Branch
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 1004
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  pd23n@nih.gov

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.866 (NIA), 93.242 (NIMH), and 93.853 (NINDS).  Awards are made under
authorization 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 grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This
program is not subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.

Note that there is a new publication of the NIH Grants Policy Statement published
in the NIH Guide for Grants and Contracts on October 21, 1998 and available at
http://www.nih.gov/grants/guide/notice-files/not98-146.html

The PHS strongly encourages all grant and contract 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 people.


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