Subject: NIH GUIDE - Vol. 20, No. 10, March 8, 1991 - RFA AG9110
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Fri, 08 Mar 91 08:49 EST

Hi Paul,
   Please post this one as: RFAAG-91-10.910308
                           Dottie
 ---------------------------- Text of forwarded message -----------------------
 
$$XID RFA AG9110 AG-91-10 P1O1 *****************************************
 
REQUEST FOR COOPERATIVE AGREEMENT APPLICATIONS
 
COOPERATIVE CLINICAL STUDIES FOR THE TREATMENT OF COGNITIVE
IMPAIRMENT AND BEHAVIORAL DISORDERS ASSOCIATED WITH ALZHEIMER'S
DISEASE
 
RFA:  AG-91-10
 
P.T. 34; K.W. 0715180, 0414005, 0715020, 0795005, 0740020
 
National Institute on Aging
 
Letter of Intent Receipt Date:  April 1, 1991
Application Receipt Date:  May 21, 1991
 
SUMMARY
 
The National Institute on Aging (NIA) is inviting cooperative
agreement (U01) applications from established clinical
investigators to organize and conduct multi-site clinical studies
on the efficacy of a number of compounds in ameliorating
cognitive impairment and non-cognitive behavioral disorders of
Alzheimer's disease.  Each applicant should organize a group of
investigators and institutions that is capable of screening and
clinically evaluating compounds to determine those that should be
studied in more formal and extensive double-blind clinical
trials. A Clinical Data Coordinating Center is to be included and
will provide data management, reporting services, data analysis,
and overall study coordination and management.  An Oversight
Group, appointed by NIA and supported separately from the
Cooperative Agreement, will meet regularly to evaluate issues of
safety, efficacy, scientific integrity, and compound selection.
 
There are no present plans to reissue this Request for
Applications (RFA) at any future time.  The NIA intends to invite
a competitive continuation application as a cooperative agreement
upon expiration of the initial funding period, contingent on the
continued availability of funds for this purpose.
 
Other institutes within the National Institutes of Health and
the Alcohol, Drug Abuse, and Mental Health Administration have
an interest in research dealing with treatments for Alzheimer's
disease and related dementias including the National Institute
of Neurological Disorders and Stroke and the National Institute
of Mental Health
 
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 about 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 to the affected individual and the
families and raises many complex social and economic issues for
the country.
 
AD provides a complex neurochemical puzzle, and present efforts
to treat it have not yet produced any reliable compounds.  The
U.S. Congress has recognized this problem, and as part of the
FY91 appropriation for the National Institute on Aging, has
mandated that NIA "explore new treatment and management methods,
including testing promising drugs, such as nerve growth factor
and acetylcarnitine, that could safely and effectively slow or
reverse the symptoms of Alzheimer's disease."
 
The NIA has responded to the Congressional language and the need
for a broader research effort in two ways.  The goal of a
companion RFA (AG-91-09) is to promote the development of a
broader range of potentially efficacious compounds beyond the
current well-established effects of cholinesterase inhibitors and
cholinergic agonists.  The goal of this RFA is to evaluate the
efficacy of a number of compounds in short-term clinical studies
as a preliminary measure to fully developed long-term clinical
trials.
 
The etiology of AD is not known, and the pathobiological
processes that underlie the steady progression of the clinical
course of this disease are not well 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, and elements of the oxidative and
cellular energy metabolism processes.  The hallmark of the
disease involves progressive cell dysfunction, cell loss, and the
accumulation of a wide variety of protein and
cytoskeletal abnormalities.  At present it is not known when and
how the degenerative process begins; for example, it is not clear
whether fragments of amyloid protein initiate the degenerative
process or the formation and accumulation of the protein is the
end result of gradual cell atrophy and death initiated by some
other agent or process.
 
At present there are no generally safe and effective treatments
for AD. The few agents that are available have demonstrated only
modest effects in slowing the rate of progression of the
cognitive decline for short periods in subsets of patients.  The
majority of the compounds considered candidate drugs have been
developed primarily for other disorders and have generally been
designed to modify the synthesis, release, or degradation of
neurotransmitters.  Most of the agents have been targeted towards
the cholinergic system which is an especially vulnerable neural
population in AD and cognitive function.
 
In addition to pharmacological modification of the cognitive
impairment associated with AD, the NIA is interested in
pharmacological interventions that can reduce the non-cognitive
secondary symptoms which are frequently seen in the course of AD
and are reported as important contributors to decisions to
institutionalize.  These include but are not limited to such
behaviors as agitation, verbal and physical aggression, disturbed
sleep, depression, wandering, pacing, screaming and other
inappropriate vocalizations, and delusions.  The focus of these
trials would be on pharmacological interventions which change the
clinical course and manifestations by interrupting or alleviating
the symptoms of the disease and are not simply chemical
restraints on the patient's behavior.
 
The paucity of any compounds which can uniformly slow or reverse
the progression of the disease or ameliorate the symptoms
requires that the most creative scientific talents in all
relevant scientific disciplines and organizations be mobilized
into groups which will aggressively pursue a concerted effort to
discover compounds and strategies for the treatment of the
disease.  Agents are needed which can ameliorate the symptoms of
the disease even for a short time, because such agents would
provide needed relief, however brief, to the victims and their
families.
 
The discovery and development of new compounds is delineated in a
separate RFA (AG-91-09).  Beyond the discovery of new compounds,
a strategy must be implemented so that new compounds can be
rapidly and efficiently taken from the laboratory bench to the
clinic. Thus, research is invited to provide a mechanism to
rapidly and simultaneously evaluate a number of compounds for
efficacy in clinical studies in order to determine which are the
most promising to be taken into full-scale double-blind trials.
 
II. OBJECTIVES AND SCOPE
 
The objective of this RFA is to support cooperative multi-site
clinical studies to evaluate a number of compounds for efficacy
in ameliorating the cognitive impairment and non-cognitive
behavioral disorders associated with Alzheimer's disease to
determine which compounds should go on to long-term clinical
trials.  This initiative is intended to stimulate high risk
efforts to test novel compounds which go beyond those already
underway or likely to be undertaken by pharmaceutical firms in
the foreseeable future.  The goal of this effort is not to
duplicate or compete with pharmaceutical companies but to
complement and accelerate the process of evaluating new effective
treatments for Alzheimer's disease. The aim is to encourage
innovative approaches to the treatment of AD.
 
Because of the need for a large and diverse base for patient
recruitment and study, it is expected that there will be one
primary applicant site and a number of cooperating sites to be
supported by subcontract or consortium agreements.  Each of these
sites is referred to as an Alzheimer's Disease Study Unit (ADSU).
The Clinical Data Coordinating Center, to be included in this
RFA, will provide data management, reporting services, data
analysis, and overall study coordination and management.   This
central coordinating service function may be provided by an
organization that contains an ADSU or at a separate site
supported by a subcontract or consortium agreement.
Plans for subcontract or consortium agreements must be fully
documented as indicated in Section IX, "MINIMUM REQUIREMENTS FOR
APPLICATION."
 
An Oversight Group, to be appointed by NIA and supported
independently from the Cooperative Agreement, will meet regularly
to evaluate issues of safety, efficacy, scientific integrity, and
compound selection.  They will make their recommendations to the
Steering Committee which will be composed of the Principal
Investigator, the Directors of each of the ADSUs and the
Director of the Clinical Data Coordinating Center, and the NIA
Program Administrator.
 
The clinical studies must be well-designed with adequate power
estimation so that the information is statistically
reliable and clinically useful in identifying efficacious
compounds.  However, the studies need to be designed in such a
manner that the data can be obtained in a relatively short period
of time in order to be able to evaluate many compounds and
determine which have promise for further testing. The final
strategies and definitive protocol will evolve during the
planning phase from the deliberations of the investigators with
the assistance of the NIA Program Administrator.  However, the
application should include a sample protocol utilizing a compound
likely to be studied such as nerve growth factor,
acetylcarnitine, deprenyl, DU996, or another of the
applicant's choosing, to demonstrate the applicant's originality,
uniqueness, and scientific and technical expertise.
 
This process should also include the development of new
assessment methodologies and instruments for evaluating clinical
improvement and activities of daily living.  Assessment of any
new instruments may be included as part of the clinical
studies, but the end point of the studies should involve
instruments generally accepted by the scientific community.
The choice of which compounds to evaluate will also be made
jointly by the investigators and the NIA Program Administrator
with the concurrence of the Oversight Group.
 
The development of protocols for add-on studies to currently
existing clinical drug trials that would be designed to provide
additional data is also encouraged under this RFA.
 
The participating investigators will be primarily responsible for
the development and refinement of the protocols through
collaboration with one another and with assistance by the NIA
Program Administrator.  The Principal Investigator and Directors
of each ADSU and the Coordinating Center will meet in Bethesda,
Maryland, approximately six times in the first year, as needed to
develop and refine the protocols, and every 6 months thereafter.
Data from each protocol will be collected by the Data
Coordinating Center.  Regular progress reports will be made
available to the Steering Committee and the Oversight Group.  The
protocol for each compound studied will define the rules
regarding access to data and publications.
 
III. STUDY ORGANIZATION
 
The cooperative clinical studies will include a number of ADSUs
and a Clinical Data Coordinating Center. A Steering Committee
will be established and, acting by consensus, will plan,
implement, and evaluate all aspects of the studies.  This will
include choosing compounds for study, guiding data analysis,
interpreting results, and generating written reports. The ADSUs
will recruit, evaluate and treat the participants in the clinical
studies. An Oversight Group will meet regularly to evaluate
issues of safety, efficacy, scientific integrity, and compound
selection and will make recommendations to the Steering
Committee.
 
The outline presented below is a guideline for
discussion by the applicants and provides a basis for
budgeting for the application. It is expected that these will
be prospective, randomized studies, comparing one or more new
compounds with a control.
 
The ADSUs will plan for the following:
 
1)  to address therapy(ies) and clinical strategy(ies)
recommended for investigation to alleviate cognitive impairment
and non-cognitive behavioral disorders.  All ADSUs will be
expected to follow the final common protocol developed for each
compound to be tested;
 
2)  to define patient characteristics, entry criteria,
recruitment procedures, and randomization methods for assigning
patients to treatment and control groups;
 
3)  to agree not to report data prior to the collaborative
reporting of the data;
 
4)  to define the available patient pool;
 
5)  to recruit an adequate number of well-characterized patients;
 
6)  to manage patients clinically;
 
7)  to maintain patient records, as required by the common
protocol;
 
8)  to control and document the quality of clinical care,
clinical, laboratory, and patient data; and
 
9)  to provide evidence for their experience in previous
clinical studies.
 
The proposal must include a Clinical Data Coordinating Center
which can be associated with or separate from an ADSU site. This
Center will have primary responsibility for quality control and
uniformity of data collection, and management of the collective
data base including editing, storing, and analyzing data, and
generating reports.  The Center will assist in writing, with
other investigators and the NIA Program Administrator, each
clinical protocol and manual of operations.  The Center will also
assist in the executive secretariat function of managing the
writing committee (which will be organized by the Steering
Committee) for the purpose of reporting results in appropriate
fashion and in the appropriate media. The proposal should include
details of the establishment and operation of this Center.  In
staffing and in preparing the budget, applicants can assume that
this Center will be responsible for all aspects of data handling
and that the ADSUs will not otherwise need to include
individual(s) involved in processing and manipulating data.
 
The Clinical Data Coordinating Center should describe fully the
following:
 
1. Data management:  plan for management and coordination of all
ADSUs relative to flow of data and information; reports to be
generated; plans for data management, i.e., entering, editing,
and storing data, developing and printing forms, protocols, and a
manual of operations.
 
2. Plans for patient randomization.
 
3. Plans for monitoring and coordinating the performance of the
ADSUs.
 
4. Plans for quality control, including clinical data, laboratory
data, and protocol adherence.
 
5. Projected plans and methods for statistical analysis and
formulating reports.
 
6. Plans for assisting in the activities of the writing
committee.
 
IV. STUDY PROTOCOLS
 
The sample protocol should be written to meet the objectives and
scope of this Request for Applications (RFA). Applications should
be for a maximum term not to exceed 5 years. The protocol should
include a study designed to test the efficacy of a compound in
the treatment of cognitive impairment and/or non-cognitive
behavioral disorder. The sample protocol submitted with this
application, utilizing one of the compounds indicated above (i.e.,
nerve growth factor, acetylcarnitine, deprenyl, DU996) or another
of the applicant's choosing, will be used to evaluate the
adequacy of the applicant's approach to the development and
evaluation of a clinical study and the applicant's understanding
of the problems associated with diagnosing, evaluating, and
assessing cognitive impairment and non-cognitive behavioral
disorders in AD. The protocol should be designed
to allow compatibility among ADSUs.  Because the actual studies
will be designed through a consensus process, it is understood
that the final protocols may differ from the sample.
 
V. DEFINITIONS
 
COOPERATIVE AGREEMENT (U01) - An assistance mechanism in which
substantial programmatic involvement with the recipient
organizations during the performance of the planned activity is
anticipated.
 
ALZHEIMER'S DISEASE STUDY UNIT (ADSU) -
Organizations actively involved in the treatment of Alzheimer's
disease join together with a common goal of studying the efficacy
of a number of compounds in ameliorating cognitive deficits and
non-cognitive behavioral disorders.
 
PRINCIPAL INVESTIGATOR (PI) - The person who, in addition to the
responsibilities traditionally assumed under this position (see
PHS Grant Policy Statement, revised October 1, 1990), directs the
ADSUs. The PI should be a physician who has substantial
experience both in 1) diagnosis, assessement, and treatment of
Alzheimer's disease and 2) in performance of clinical studies.
The PI is responsible for both the initial submission and for all
aspects of the performance of the individual ADSUs.  The PI will
direct the research activities of his/her ADSU and coordinate the
scientific and administrative operations of the other ADSUs and
the Data Coordinating Center with the Directors of the ADSUs and
the Center. If an award is made, the PI's institution (awardee)
is legally and fiscally accountable for the disposition of funds
awarded to all ADSU and Clinical Data Coordinating Center
components.
 
NIA PROGRAM ADMINISTRATOR - The member of the professional staff
of the NIA who functions as a peer with the PI and ADSU and
Coordinating Center Directors and assists aspects of the
cooperative relationship between NIA and the ADSUs as described
in Section VIII, "TERMS OF AWARD."
 
STEERING COMMITTEE - A Steering Committee (SC) will be
established whose voting members will consist of the PI, the
Directors from each of the participating ADSUs or their
designates, the NIA Program Administrator, and the Director of
the Data Coordinating Center. This Committee will be responsible
for all aspects of the planning, implementation, and evaluation
of the cooperative clinical studies, including: designing the
protocols, choosing compounds to be studied, guiding data
analysis, interpreting results, generating written reports
(through implementation of a writing committee), and clearing
publications before submission to journals.
 
The chairperson of the Steering Committee will be the PI.  The
first meeting of the Steering Committee will be convened by the
NIA Program Administrator.  It is estimated that up to six
meetings will be needed in the first year to develop and finalize
the first protocol.  Thereafter, meetings will be approximately
semi-annually.  All major scientific decisions will be made by
the Steering Committee with the advice of the Oversight Group.
 
CLINICAL DATA COORDINATING CENTER - The centralized data
management required for collecting, editing, storing, and
analyzing data and generating reports will be established through
the Data Coordinating Center which will have its own Director.
Center personnel will provide appropriate biostatistical
experience and expertise and be responsible, along with the PI,
for writing, in collaboration with other investigators and the
designated NIA Program Administrator, each protocol and manual of
operations. The Coordinating Center will provide to the other
participating investigators and the NIA detailed reports of
accumulating data and ADSU performance at 6-month intervals. In
addition, it must provide such interim analyses as deemed
appropriate by the Steering Committee.
 
The Coordinating Center, in addition to providing the data
management, will also provide overall management and coordination
of the studies. This could include such things as arranging for
the quality control of assessment instruments in the ADSUs as
may be decided in the planning phase.
 
The Coordinating Center will assist the PI in the executive
secretariat function of managing the writing committee for the
purpose of reporting results in appropriate fashion and in the
appropriate media.
 
OVERSIGHT GROUP -  The Oversight Group, to be appointed by NIA
and supported independently from the Cooperative Agreement, will
meet regularly to evaluate issues of patient safety, compound
selection, compound efficacy, and scientific integrity. The
Oversight Group will make recommendations to the Steering
Committee. The Chairman or representative of the Steering
Committee and the NIA Program Administrator will participate as
observers of the Oversight Group.
 
PROJECT COORDINATOR - An individual, associated with the
applicant organization, who has substantial administrative
experience in managing patient enrollment and follow-up and
multi-source data collection of clinical trial data.
 
ARBITRATION PANEL - A group consisting of one person selected by
the Principal Investigator, one person selected by the NIA
Program Administrator, and a third person selected by these two
members. The interaction of this panel is detailed in Section X.
TERMS OF AWARD.
 
VI. MECHANISM OF SUPPORT
 
A. The award will be made as a COOPERATIVE AGREEMENT (U01). In
awarding the Cooperative Agreement, NIA anticipates substantial
involvement of a designated Program Administrator during
performance of the award. The nature of NIA staff assistance to
the awardee is described in Section VIII of this RFA under "TERMS
OF AWARD: NATURE OF PARTICIPATION OF NIA STAFF". There is no
intent, real or implied, for the NIA Program Administrator to
direct activities or to limit the freedom of investigators.
 
B. NIA has set aside up to $3.25 million total costs for the
first year of funding. Funding of one award is anticipated. The
starting date for the initial annual period will be on or before
September 30, 1991. The NIA may invite a competitive continuation
application upon expiration of the initial funding period,
contingent on the continued availability of funds for this
purpose and the continued need for the study and for staff
involvement.
 
C. The award will be made to a successfully competing applicant
institution serving as home base for a particular ADSU, as
explained in further detail in Section IX. B.
 
D. Except as otherwise stated in this RFA, the award will be
administered as described in the Public Health Service Grants
Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised
October 1, 1990.
 
E. Although this program is provided for in the financial plans
of NIA, the award of a cooperative agreement pursuant to this RFA
is also contingent upon the continuing availability of funds for
this purpose.
 
VII. ELIGIBILITY REQUIREMENTS
 
To assure compliance with United States regulatory policy,
applicant institutions are limited to those in the United States.
An applicant institution may be a university, medical college,
hospital or clinic.
 
VIII. TERMS OF AWARD: AWARDEE RIGHTS AND RESPONSIBILITIES AND
NATURE OF PARTICIPATION OF NIA STAFF
 
The special "TERMS OF AWARD" described in this section are in
addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines; HHS grant administration regulations
45 CFR Part 74 and other HHS, PHS, and NIH grant administration
policy statements. Assistance via Cooperative Agreement differs
from the traditional research grant in that, in addition to the
normal programmatic and administrative responsibilities, the
component awarding the Cooperative Agreement anticipates
substantial involvement of a designated Program Administrator
during performance of the project.
 
Cooperative Agreements are subject to the administrative
requirements outlined in applicable OMB circulars, and all
pertinent HHS, PHS, and NIH grant regulations, policies and
procedures, with particular emphasis on PHS regulations
at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74.  The
following terms and conditions pertaining to the scope and nature
of the interaction between the NIA Program Administrator and the
investigators will be incorporated in the Notice of Award. These
terms will be in addition to the customary programmatic and
financial negotiations which occur in the administration of
grants.
 
A. AWARDEE RIGHTS AND RESPONSIBILITIES
 
The PI defines the details for the project within the guidelines
of the RFA, retains primary responsibility for the performance of
the scientific activity, has the primary responsibility for
publications emanating from these studies, and agrees to accept
assistance from the NIA Program Administrator in the scientific
and technical management of the studies as indicated below under
"NATURE OF PARTICIPATION OF NIA STAFF."
 
The PI, each ADSU Director, and the Coordinating Center
Director (or their designees) will be responsible for attending
all Steering Committee meetings. The frequency of meetings (about
six meetings during the first year and two per year thereafter)
shall be determined by the Steering Committee which will be
responsible for scheduling the time and place. NIA will be
represented by the Program Administrator who will be a member of
the Steering Committee.
 
Cooperative Participation and Quality Control  -  The
investigators will, in a cooperative fashion, define objectives
and approaches, design and implement the protocols, select the
compounds to be studied with the advice of the Oversight Group,
conduct the studies, collect and analyze the data, and publish
the results, conclusions and interpretations, of the study.  Each
ADSU will follow the procedures required by the consensus
protocol generated by the Steering Committee regarding patient
selection and management, data collection, and quality control.
 
Publications  - Publications or oral presentations of any
analysis of data created under this agreement will fully involve
and appropriately recognize the ADSUs, the Data Coordinating
Center, and the NIA Program Administrator. Most analyses will be
initiated by the Steering Committee. Groups of individuals
performing local analyses will be encouraged to inform the
Steering Committee of any analysis prior to initiation in order
to avoid duplication. Approval of the Steering Committee will be
required for all analyses prior to publication or presentation
according to criteria which will be developed by the Steering
Committee.
 
Data Management  -  The ADSUs will be responsible for providing
the Clinical Data Coordinating Center with all primary study data
for management and analysis using procedures determined by the
Steering Committee.  Specific analyses will be directed by the
Steering Committee. The data, and their analyses and
interpretations by the Coordinating Center, exist for the use of
the ADSU investigators and not for the NIA or the Government.
The awardee institution will retain custody of and primary rights
to the data, consistent with current HHS, PHS, and NIH policies.
 
B. NATURE OF PARTICIPATION OF NIA STAFF
 
It must be emphasized that, by nature of the Cooperative
Agreement, the NIA Program Administrator will assist, but not
direct, the cooperative clinical studies' activities. These
activities include facilitating the development of study
protocols, implementation of the study, and the analysis and
interpretation of data. Additionally, the NIA Program
Administrator may contribute, through review, comment, analysis
and co-authorship (where appropriate), reporting of results to
the community of investigators and health care recipients.
 
Monitoring  -  There will be periodic on-site monitoring of each
ADSU by the NIA Program Administrator.  Such on-site visits will
include, in part, monitoring the following: compliance with
protocol specifications; quality control and accuracy of data
recording; and protocol accrual. The Government, via the NIA
Program Administrator, will have access to data generated under
this Cooperative Agreement and may periodically review the data
and progress reports. Information obtained from the data may be
used by the NIA Program Administrator for preparing of internal
reports on the activities of the studies. However, the awardee
will retain rights to the data as indicated above, and timely
publication of major findings is encouraged.
 
The Oversight Group will meet regularly to evaluate issues of
patient safety, compound selection and efficacy, and scientific
integrity.  They will make their recommendations to the Steering
Committee.
 
Organizational Changes  - Certain ADSU organizational changes
must have the prior written approval of the NIA Grants Management
Officer in consultation with the Program Administrator.  These
changes include key personnel and the deletion of a component.
 
Program Review  -  In addition to any special reports and
stipulations described herein, reporting requirements will be
identical to those currently in existence for awardees of
traditional NIH research project grant awards, i.e., annual
progress reports must be submitted.  A suggested format developed
by program staff for this purpose will be provided. Program staff
will review the progress of each ADSU and the Coordinating Center
through consideration of the ADSU and Coordinating Center annual
reports, program site visits, and patient logs.  This review may
include, but not be limited to, compliance with the protocols,
meeting patient enrollment targets, adherence to uniform data
format, number of new patients available, and timeliness and
quality of data reporting.
 
Inability to meet the performance requirements set forth in the
above TERMS OF AWARD, or significant changes in the level of
performance, may result in an adjustment of funding, withholding
of support, suspension or termination of the award.
 
C. ARBITRATION PROCESS
 
The details of arbitration procedures pertaining to the scope and
nature of the interaction between NIA and the participating
ADSUs will be incorporated as special terms and conditions into
the Notice of Grant Award. The arbitration procedures will be
invoked only when agreement cannot be reached between the awardee
and the NIA Program Administrator on programmatic decisions
regarding scientific-technical issues that may arise after the
award.  In that event, an Arbitration Panel will be formed
consisting of one person selected by the Principal Investigator,
one person selected by the NIA Program Administrator, and a third
person selected by these two members. The decision of the
Arbitration Panel will be binding.
 
The special arbitration procedures described above in no way
affect the awardee's right to appeal an adverse action in
accordance with PHS regulations at 42 CFR Part 50, Subpart D, and
HHS regulations at 45 CFR Part 16.
 
IX. MINIMUM REQUIREMENTS FOR APPLICATION
 
Applicants seeking funding under the cooperative clinical studies
must meet the following requirements:
 
A) The application must name a single PI who is an employee of
the applicant institution and who will be responsible for the
application as well as all ADSU-related research activities. The
PI must be a physician who has substantial experience in 1)
diagnosis, assessment, and treatment of Alzheimer's disease; and
2) in performance of clinical studies.
 
B) The application must identify the single applicant
organization (grantee institution) that will be legally and
financially responsible and accountable for the use and
disposition of funds awarded on the basis of this RFA to itself
and to other institutions housing ADSUs or the Data Coordinating
Center; it also must show availability of personnel and
facilities capable of performing and supporting the
administrative functions of the proposal.
 
C) The application must name a Project Coordinator who is an
individual with substantial administrative experience in managing
patient enrollment and follow-up, and multi-source data
collection of clinical studies.
 
D) The collection of ADSUs should be composed such that
redundancies of elements such as administration, study personnel,
and ancillary personnel will be limited.
 
E) The application must provide a clear, concise plan in
narrative and diagrammatic form that depicts the
interrelationships among the ADSUs and the contribution of each
to fulfillment of overall objectives; it also must include an
organizational chart showing the names, organizations, and
scientific disciplines of the Principal Investigator, ADSU
Directors, Coordinating Center Director, and other key personnel.
 
F) The application should indicate criteria for consideration of
potential additional ADSU sites to be added on at later times.
 
G) The application must provide a plan to ensure the maintenance
of close cooperation and effective communication among the ADSUs
and Coordinating Center and a statement accepting the TERMS OF
AWARD as indicated in Section VIII.
 
H) ADSUs must document access to a sufficient population of
patients with Alzheimer's disease.
A description of the currently available population
should be presented.
 
I) The application must ensure that the applicant institution and the
other sites involved have written policy guidelines in place on
financial conflict of interest and the avoidance thereof as prescribed
in the PHS Grants Policy Statement [DHHS Publication No. (OASH)
90-50,000, revised October 1, 1990] and 45 CFR Part 74, Subpart P. This
is intended to preclude any potential conflict of interest of
investigators with relationships with and holdings in for-profit
pharmaceutical, biotechnology, or venture capital companies.
 
J) The application should indicate plans for the development and
testing of new assessment methodologies and instruments for
evaluating clinical improvement and activities of daily living.
 
K) The applicant should present full plans for subcontract or
consortium agreements, documenting capabilities of cooperating
institutions and investigators and plans for organizational and
working arrangements among them.
 
L) As indicated in Section IV, "STUDY PROTOCOLS", a sample
protocol must be presented addressing research questions for the
study so that the scientific and technical merit can be
evaluated.
 
M) 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.  In such a case, a letter
of agreement from either the GCRC program director or Principal
Investigator must be included with the application.
 
N) FEDERALLY MANDATED REGULATORY REQUIREMENTS
 
Each ADSU is required to meet the Department of Health and Human
Services (HHS)/Public Health Service (PHS) regulations for the
protection of human subjects and FDA requirements for the conduct
of research using investigational agents. At a minimum, these
include:
 
o methods for assuring that each institution at which ADSU
investigators are conducting clinical studies has a current,
approved assurance on file with the Office for Protection from
Research Risks (OPRR); that each protocol is reviewed by the
responsible Institutional Review Board (IRB) prior to patient
entry; and that each protocol is reviewed annually by the IRB as
long as the protocol is active;
 
o methods for assuring or documenting that each patient (or
patient's legal guardian) gives fully informed consent to
participation in a research protocol prior to the initiation of
the experimental intervention.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF
NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA 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, 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.  This information should be included in the form
PHS 398 in Section 2, A-D of the Research Plan AND summarized in
Section 2, E, Human Subjects.
 
Applicants/offerors 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.
 
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.
 
X. BUDGETING
 
Each applicant should submit an adequately justified budget for
each 12-month segment for 5 years. Estimates of staffing needs,
including the Principal Investigator, ADSU Directors,
Coordinating Center Director, and support staff, must be
submitted.
 
The proposed budget must include any and all expected costs
associated with study participation. The proposed budget must
include additional funds for expenses such as shipment of data and
travel to cooperative group meetings as described in Section VIII
under Awardee Rights and Responsibilities. Data will be requested
in a hard copy/electronic format to be determined by the Data
Coordinating Committee. Appropriate budget adjustments will be
made when the method of data shipment is known.
 
Activities during the initial period of protocol development may
require a relatively small proportion of staff time, mainly
of the Principal Investigator, project coordinator, ADSU
Directors, Coordinating Center Director, and one or two key staff
members such as nurse-coordinators. It is anticipated that
these individuals may need to attend up to six meetings
in Bethesda, Maryland, during the first year.
 
For patient recruitment, study, and data analysis, detailed
budget estimates must be based on the proposed research
plan developed using guidance in this RFA. Meetings would
probably continue to be held semi-annually.
 
The study will conclude with follow-up on the last patients,
close-out costs, final data analyses, and activities of the
writing committee needed to report the final results of the
trials.
 
XI. REVIEW PROCEDURES AND PEER REVIEW CRITERIA
 
A. REVIEW PROCEDURES
 
Applications will be reviewed by NIA staff to determine
administrative and programmatic responsiveness to this RFA; those
judged to be nonresponsive will be returned to the applicant
without review.  Those applications that are complete and
responsive may be subjected to a preliminary review by a
subcommittee of the review group to determine those applications
deemed to be competitive.  Those applications judged to be
noncompetitive for award will be withdrawn from further
competition.  Those applications judged to be competitive will be
further reviewed for scientific and technical merit by a special
review committee convened by the Scientific Review Office, NIA.
Following review by an initial review group, the application will
be considered by the National Advisory Council on Aging.
 
All applications must be complete in themselves.  Because it is
unlikely that site visits will be conducted, each application
should be prepared as if no such visit will occur.
 
In preparing applications, applicants should follow the
instructions for form PHS 398 (revised 10/88, reprinted 9/89) and
the specific supplemental instructions included in this RFA.  All
IRB approvals must be complete and submitted with the application
or received within 60 days after the application receipt date or
three weeks before the scientific review, whichever comes sooner.
It is incumbent upon the applicant to ensure that the Executive
Secretary receives all clearances by the established deadline or
the application will not be reviewed.
 
B.  REVIEW CRITERIA
 
Applications will be judged primarily on scientific merit
and on the discussion of considerations
relevant to the proposed clinical investigations.  The successful
applicant will be selected on the basis of scientific excellence,
experience of the investigators, capability to perform the work
proposed, availability of eligible well-characterized patients,
demonstrated prior experience in performing clinical drug studies
in Alzheimer's disease, experience in coordinating and managing
data collection and analysis, and a demonstrated willingness to
accept NIA assistance under the terms of award mentioned above in
Section VIII.
 
Applicants should indicate how they will develop the logistics
for coordinating the ADSUs including inter-relationships among
the institutions involved and should indicate criteria for
consideration of potential new ADSUs.
 
The application must be directed toward the attainment of the
stated programmatic goals (see Section II). Evaluation of
applications will consider the quality of the whole and its
potential for accomplishing the objectives of this RFA as well as
the quality of individual components.
 
The following factors will be considered important in the
scientific and technical review of the clinical studies aspect of
the application:
 
1. the relevance of the applicant's objectives to the design and
evaluation of clinical studies in Alzheimer's disease;
 
2. the scientific and technical merit of the approaches used and
the significance, originality and uniqueness of the sample
protocol submitted utilizing one of the compounds indicated above
or another of the applicant's choice with the understanding that
the final protocols may differ from the sample;
 
3. the specific competencies of the PI, ADSU Directors, and other
key personnel to conduct the proposed work including the
following: research experience, specifically experience in
conducting and evaluating clinical pharmacological research with
Alzheimer's disease patients; clinical research experience in
assessing cognitive impairments and non-cognitive behavioral
disorders in Alzheimer's disease; competence, commitment, and
time availability of all key personnel;
 
4. the available patient pool and, preferably demonstrated by past
experience, the ability to recruit, study,
and maintain an adequate number of patients to achieve
statistically meaningful answers to study questions;
 
5. maintaining and sharing clinical data as required by the
common protocol;
 
6. procedures for adherence to standardized protocols and to
continued compliance with requirements of the study design;
 
7. mechanism to ensure collaboration among the ADSUs, the
Coordinating Center, and the NIA Program Administrator;
 
8. adequate clinical space and supportive environment including
evidence of institutional support for participation in a long-
term collaborative study;
 
9. appropriateness of the budget for the work proposed.
 
Criteria for review of the Clinical Data Coordinating Center will
include the following:
 
1. Qualifications and experience of key personnel including
     o scientific, administrative and statistical abilities of
       the investigators;
     o experience of the investigators in data management and
       analysis;
     o experience in managing and coordinating other clinical
       investigations;
     o ability to devote adequate time to the effective conduct
       of the study.
 
2.   Plans for data management including
     o Coordinating all ADSUs relative to flow of data and
       information;
     o Reports to be generated;
     o Editing and storing data;
     o Preparation, testing and validation of data collection
       forms;
     o Preparation of the manual of operations.
 
3.   Plans for patient randomization and statistical methodology
and analysis.
 
4.   Plans for monitoring and coordinating the performance of
ADSUs, laboratory or test instrument evaluations, and quality
control and analysis.
 
5.   Facilities including computer and data management.
 
6.   Plan for generating reports and assisting in the activities
of the writing committee.
 
7.   Appropriateness of the budget for the work proposed (see
above for information about phases).
 
Applicants must also demonstrate:
 
1. A documented commitment of institutions represented by
investigators; documented capability of Principal Investigator's
institution to serve as Central Operations Office for the ADSUs
and Coordinating Center.
 
2. A written Commitment to accept the participation and
assistance of the NIA Program Administrator in accordance with
the guidelines outlined under Section VIII, "TERMS OF AWARD:
NATURE OF PARTICIPATION OF NIA STAFF."
 
3. A mechanism for selecting and replacing key professional or
technical personnel using the framework of the RFA.
 
4. An ability to conform to Section IX, "MINIMUM REQUIREMENTS FOR
APPLICATION".
 
5. Agreement to Section III, "STUDY ORGANIZATION".
 
XII. METHOD OF APPLYING
 
A.  The application must be submitted on the 10/88 revision
(reprinted 9/89) of the form PHS 398.  To identify applications
as being responsive to the RFA, check "yes" on item 2 of page 1
of the application and enter the title:  "NIA:Clinical Studies
for AD"  and the RFA number (AG-91-10).  The mailing label
available in the 10/88 revision (reprinted 9/89) of the form 398
must be used and the RFA label must be stapled to the bottom
of the face page.  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.
 
B.  Before preparing an application, the prospective applicant
should carefully read the NIA Information Brochure on Program
Project and Center Grants. The Information Brochure may be
obtained from Dr. Neil Buckholtz or the Chief, Scientific Review
Office (SRO) at the
addresses given below.  The Information Brochure contains special
instructions for preparing multi-project applications, review
procedures, review criteria, and other important information. It
is important to follow the instructions for preparing the
application as outlined in the Information Brochure as well as
the specific supplemental instructions in this RFA.  Failure to
do so may result in an application with insufficient information
for appropriate scientific review. Questions regarding
instructions in the brochure or responsiveness to the RFA should
be directed to Dr. Neil Buckholtz.
 
C.  Organization of Application and Suggested Modifications of
form PHS 398 (revised 10/88, reprinted 9/89).
 
This RFA requires the submission of a single application for the
proposed cooperative clinical studies in Alzheimer's disease.
Because of the potential multi-institutional nature and the
special requirements in this RFA, additional questions regarding
format and/or budget can be directed to Dr. Buckholtz and Mr.
Ellis (see below).
 
The special requirements of this RFA will also necessitate
the following modification: the Introductory Section must
apply to the proposal as a whole with respect to goals,
objectives, and overall research plan.
 
The Introductory Section, not to exceed 2 pages, must
contain any additional information about the proposed PI or
his/her institution as evidence of capability to carry out the
scientific and administrative duties required in this RFA and the
functions of the Central Operations Office.
 
In addition, the Introductory Section must include information
concerning the elements in Section IX of this RFA (particularly
Parts A, B, E, and F) and a statement of acceptance of the
provisions of Section VIII.
 
Although not a prerequisite for applying, potential applicants
are encouraged to submit a non-binding letter of intent by April
1, 1991 to Dr. Buckholtz at the address below.  It should
indicate the PI and other key personnel, the applicant site and
other potential ADSU and Data Coordinating Center sites.
The letter of intent is not mandatory and does
not influence review or funding decisions, but it will enable the
NIA to plan the review, and will ensure that each potential
applicant receives relevant program information prior to
expending considerable effort in application preparation.
 
Applications must be complete and received by May 21, 1991 for a
start date on or before September 30, 1991.  If received late,
the application will be returned without review.
 
Application kits may be secured from institutional offices of
grants and contracts and from:
 
Office of Grants Inquiries
Division of Research Grants
National Institutes of Health
Westwood Building, Room 449
Bethesda, MD  20892
 
Mail the complete application and four copies to:
 
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
To expedite review, two exact copies should be sent to:
 
Chief, SRO, OEA, NIA, NIH
Building 31, Room 5C12
9000 Rockville Pike
Bethesda, MD  20892
 
XIII. INQUIRIES
 
Applicants are strongly encouraged to obtain supplemental
information and to discuss their plans with and direct any other
inquiries to:
 
Neil Buckholtz, Ph.D.
Program Administrator, Treatment and Management
NNA, NIA, NIH
Building 31, Room 5C35
9000 Rockville Pike
Bethesda, MD  20892
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
 
Inquiries regarding matters pertaining to the review of the
application should be addressed to:
 
Dr. Michael Oxman
Chief, SRO, OEA, NIA, NIH
Building 31, Room 5C12
9000 Rockville Pike
Bethesda, MD  20892
Telephone:  (301) 496-9666
 
Inquiries regarding fiscal matters should be addressed to:
 
Mr. Joseph Ellis
Grants Management Officer
National Institute on Aging
Building 31, Room 5C07
Bethesda, MD  20892
Telephone:  (301) 496-1472
 
**The mailing address given for sending applications to the
Division of Research Grants or contacting program staff in the
Westwood Building is the central mailing address for the NIH.
Applicants who use express mail or a courier service are advised
to follow the carrier's requirements for showing a street
address. The address for the Westwood Building is: 5333 Westbard
Avenue, Bethesda, Maryland  20816.
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.866, Neuroscience and Neuropsychology of Aging.
Awards will be made under the authority of the Public Health
Service Act, Title III, Section 301 (Public Law 78.410, as
amended; 42 USC 241) and administered under PHS grant policies
and Federal Regulations 42 CFR Part 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.