PARKINSON DISEASE NEUROPROTECTION CLINICAL TRIAL: CLINICAL CENTERS
Release Date: July 2, 2001
RFA: RFA-NS-02-010
National Institute of Neurological Disorders and Stroke
Letter of Intent Receipt Date: September 15, 2001
Application Receipt Date: Nov 15, 2001
PURPOSE
The Neurodegeneration and Clinical Trial Groups of the National
Institute of Neurological Disorders and Stroke (NINDS) request
applications for clinical centers to collaborate in the performance of
a large, double-blind randomized trial of two or more potential
neuroprotective agents in patients early in the course of Parkinson’s
disease. Applications for coordinating and statistical centers were
requested in a separate solicitation
(http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-01-012.html). The
trial was called for in the NIH Parkinson Research Agenda
(http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm). The
neuroprotectants to be tested in the trial have not yet been chosen and
will be selected by an NINDS-appointed Oversight Committee from among
those proposed by the applicants who respond to this Request for
Applications (RFA) as well as from those suggested by others, including
NINDS grantees, pharmaceutical companies, patients, and patient
advocates.
BACKGROUND
Parkinson’s disease (PD) affects nearly a million Americans, a number
that will increase over the coming decades. While available medical
therapies are usually effective for controlling symptoms for the
initial years following diagnosis, higher doses of multiple agents are
required over time, with increasing side-effects and incomplete control
of symptoms. While these treatments can dramatically improve the lives
of patients with Parkinson’s disease initially, they have been based on
dopamine replacement since the early 1970 s. They do not address the
underlying disease cause or the currently inevitable biological
progression of PD. The typical course of PD is one of gradual
worsening over a decade or more, corresponding to ongoing neuronal loss
affecting cells in the pigmented nuclei of the brain, particularly in
the substantia nigra. There is a long preclinical phase preceding
diagnosis, during which loss of these dopaminergic neurons progresses
until the threshold for clinical symptoms is reached, estimated to be
about 70-80% loss by the time of diagnosis. Given this prolonged
course of progressive neuronal loss, strategies aimed at reducing the
rates of neuronal loss or dysfunction (i.e. clinical neuroprotection or
disease-modification) are particularly important in this disorder.
Effective clinical neuroprotection would importantly reduce PD-related
disability for hundreds of thousands of Americans, prompting the
National Institute of Neurological Disorders and Stroke (NINDS) to
invite qualified investigators to submit grant applications for
components of a clinical trial aimed at identifying agents to slow the
progression of PD.
With many potential neuroprotective interventions available, clinical
trial designs in which several agents are compared to a single control
group have many advantages that may increase participant acceptance
because 1) assignment to control is less likely and 2) there is the
potential to compare directly the active interventions. Factorial
designs in which some participants may receive more than one active
intervention offer the further potential to assess effects of
combinations of neuroprotective agents that may work by different
mechanisms, (although statistical power to define interactions may be
limited). By definition, large, simple clinical trials focus on
limited goals and a few key outcomes supplementing such streamlined
protocols, subsets of participants in large, simple trials at selected
sites can be more intensively investigated.
Despite the substantial disability due to PD, few interventional
studies have evaluated agents that might retard disease progression. A
previous investigator-initiated trial supported by NINDS, Deprenyl and
Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), evaluated
selegiline (Deprenyl) and vitamin E as treatments for PD. Vitamin E
was found ineffective, and selegiline has not become widely used
because of uncertainty about a neuroprotective vs. symptomatic effect
due to an initially unsuspected dopa-agonist action.
The Parkinson Agenda for the NIH was published in April, 2000
(http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm). The
agenda calls for the initiation of randomized controlled clinical
trials to test potential neuroprotectants. Expert advice regarding
implementation of this initiative was solicited at the meeting
Therapeutic Initiatives in Parkinson Disease convened by the NINDS
(13-Oct-00, Bethesda), which included representatives of several NIH
Institutes and national experts in PD and clinical research in
neurodegenerative disorders.
RESEARCH OBJECTIVE
To demonstrate convincingly in a randomized, double-blind clinical
trial the efficacy of one or more pharmacological agents for slowing
progression of PD and to determine the toxicity and tolerability of
these agents.
Design of a clinical neuroprotection trial.
Final design of the clinical trial will result from collaboration
between and consensus of the Coordinating Center, NINDS scientific
staff, the Statistical Center, Principal Investigators from Clinical
Centers, and the NINDS Oversight Committee (see Study Organization,
below). It is anticipated that key elements of the trial will include
the following:
1) Inclusion of PD patients early after clinical diagnosis with two of
the four cardinal signs, not taking drugs that induce Parkinsonism,
absence of other disease likely to prevent 5-year follow-up. Patients
have recently started dopaminergic treatment.
2) Design capable of detection of small treatment effects because of
the clinical importance of even modest benefits to PD patients.
3) General design as a large, simple trial, including large sample
size (about 3000 participants), infrequent regular follow-up, and
limited data collection, focusing on functional and disability-related
outcomes, including those that can be assessed without direct patient
contact using either mail or telephone.
4) Prospective plans to distinguish neuroprotective effects from
occult symptomatic benefits.
The trial will involve the following phases:
1) Selection of potential neuroprotective agents.
2) Pilot studies to develop dose and safety information, to select
pharmaceutical agents useful for the main trial, and to refine outcome
measures (approximately one year).
3) Main multi-arm trial (approximately 6 years).
4) If necessary, post-trial administration of one or more apparently
efficacious neuroprotective agents to all participants to assess occult
symptomatic effects and convincingly establish neuroprotection (six
months to one year).
The entire trial may last up to eight years.
Participants in the trial will be enrolled in the earliest stages of
the disease possible, and may or may not require symptomatic therapies
(depending on the final approved study design). Based on observations
from the initial and second randomization in the DATATOP trial, it is
anticipated that there will be measurable evidence of disease
progression during follow-up averaging three to four years (extending
to five years in some participants), both in those receiving
dopaminergic agents and those who are not. Outcome instrument
development and/or adaptation of existing instruments for use with a
large, simple trial design is a key objective of the pilot phase. Use
of disability and functional outcome scales sensitive to changes seen
during the early course of PD will be emphasized as the primary
outcomes. Effects on non-motor features will be included.
Available biomarkers have not been appropriately validated to
substitute for clinical outcomes in the large phase III. Assessment of
biomarkers for screening and in selection of neuroprotective agents
will be considered. Since biomarkers as surrogate outcomes require
validation by correlation with clinical outcomes in positive clinical
trials, the concomitant assessment of biomarkers in the large
neuroprotection trial, particularly at selected centers or patient
subsets, will also be considered, balancing expense and complexity with
the overall goals of the large trial.
Several candidate agents for neuroprotection testing will likely emerge
from this RFA. Because even a small neuroprotective effect with a
minimally toxic agent would be important to detect, a relatively large
trial is required. Minimizing the cost for each participant will
permit larger numbers of participants and make it possible to evaluate
more potential neuroprotective agents. The boundary presented by large
sample sizes and the cost of conventional studies needs to be crossed
in order to obtain the initial success required to sustain research of
further neuroprotective treatments. Detecting small effects requires
large sample sizes, but it does not mandate a complex protocol.
Rather, intermediate contact by mail or telephone, allowing less
frequent clinical contact, may provide the needed data at many time
points, and reduce costs. It is anticipated that highly reliable
functional outcome or disability scales that are multi-modal can be
included to simplify outcome measures and reduce the cost of the trial.
Several design issues common to large, simple trials must be considered
and addressed. Compliance is a major concern, particularly if one or
more of the treatments being tested is generally available either over-
the-counter or through prescription. Dropouts and patients lost to
follow-up must be minimized. Inexpensive methods to maintain patient
loyalty and protocol adherence between infrequent clinic visits will be
important for successful execution. Reliable outcome measures assessed
by different clinicians and other medical professionals are necessary,
since primary care providers may have more ready access to a patient
than the neurologist. It may also be helpful to enlist the support of
PD patient advocacy groups to help build and maintain patient loyalty.
Rapid recruitment and initiation of treatment are essential,
facilitated by limited inclusion/exclusion criteria. Limited exclusion
criteria will expose a broad spectrum of PD patients to the selected
neuroprotective drugs, a likely advantage in the initial clinical
trials. (When the characteristics that predict a patient’s response to
a particular drug are not known, the chances of detecting any effect
increase if there is a wide spectrum of PD patients participating in
the study.) If neuroprotective effects are detected, further studies
may then define appropriate selection criteria. Participants will
reflect the gender and racial/ethnic composition of U.S. citizens with
PD.
Pilot data to determine the maximum safe dose for PD patients is not
likely to be available for all agents to be tested, and a pilot study
may be needed for most agents. Pilot trials should determine dose,
safety, assess the presence of a dopaminergic effect, and refine/test
outcome measures. These pilot studies may be critical to the eventual
success of the subsequent large, definitive trial. Consequently, an
initial pilot phase for testing each of the agents will be available as
part of the planning phase for the trial.
STUDY ORGANIZATION
The organizational structure will consist of the following components:
1. The Coordinating Center will develop and manage the protocol,
assure compliance with regulations, supervise and encourage
recruitment, collect, store, and maintain data from clinical centers
including recruitment and dropout data, prepare blinded reports on
adverse events, monitor study execution at clinical sites, and supply
study medications to each site. The principal investigator of the
Coordinating Center will serve as chair of the Steering Committee. The
Coordinating Center will be blinded to treatment group during
recruitment and follow-up in all trials.
2. The Statistical Center will be involved in study design, in
planning and performing analysis, and prepare all summary reports to
the Coordinating Center, Oversight Committee and NINDS-appointed Data
and Safety Monitoring Board (DSMB).
3. Clinical Centers (initially 42 sites) will recruit and follow
participants, emphasizing participant adherence and the highest
standards of protocol execution. Representatives of Clinical Centers
will selectively participate on the Steering Committee. During the
trial, Clinical Centers may be added, deactivated, or placed in a
follow-up mode with budget reduction, depending on performance and
recruitment requirements and requirements for protecting human
subjects.
In addition, there will be three key committees:
1. The Oversight Committee will be organized by the NINDS and include
NINDS clinical directors and program directors with expertise in
preclinical science of neuroprotection and in clinical trials, together
with extramural experts in PD and neurodegeneration and with
representatives of PD advocacy groups. The Oversight Committee will
give final approval to the agents to be tested, approve the final study
protocol and plans for analysis developed by collaboration between the
Coordinating Center and Statistical Center, and evaluate and approve
all protocol changes during the course of the trial.
2. The Data and Safety Monitoring Board will monitor study execution
and safety issues, and propose and consider interim analyses. It will
be appointed by the NINDS and include a non-voting NINDS representative
who will act independently of the NINDS Scientific Program Director
(see below).
3. The Steering Committee will consist of the Coordinating Center
principal investigator (who will chair the committee), the Principal
Investigator of the Statistical Center, the NINDS Scientific Program
Director, and selected members drawn from the Clinical Centers. The
specific membership and charter of the Steering Committee will be
proposed by the Coordinating Center and approved by the Oversight
Committee. The Steering Committee will approve the final protocols,
supervise overall execution of the trial, generate and approve study
policies, consider modifications of the protocol and operations, and
plan and draft study-related publications.
The NINDS will name a Program Director whose function will be to
expedite the activities outlined under Terms and Conditions (below),
and serve as representative for the NINDS to the trial components. The
NINDS Program Director will participate on the scientific committees of
the trial, but she/he will not be responsible for fiscal management of
the cooperative agreement, which will be done by a second NINDS program
scientist.
STUDY TIMETABLE
It is anticipated that one large simple randomized, placebo-controlled
clinical trial will be completed during the 8 year period of this
initiative. In addition, one or more pilot studies may be done for
each of the proposed therapeutic agents to determine safety, dose, and
feasibility parameters. Although the tentative timetable below
indicates that multiple simultaneous pilot studies succeeded by one
large simple clinical trial of multiple agents will be performed, the
actual number of protocols implemented may vary depending upon the
specific study designs agreed upon.
Year I:
o Protocol development for pilot studies (3 months).
o Patient recruitment and follow-up for several simultaneous pilot
studies (6 to 9 months). Up to 12 patients per Clinical Center (n=42)
will be recruited (total 504).
o Protocol development for the large-scale clinical trial will be
ongoing for an entire year and completed with a full manual of
operations during the last three months of the first year. The manual
of operations will be produced by the Coordinating Center in
cooperation with the Statistical Center.
Year II:
o Patient accrual will begin at 42 centers and continue for 36 months
at an average rate of two patients per month per center (total = 3024
participants).
Year III:
o Patient accrual and follow-up in the manner of a large simple trial.
Year IV:
o Patient accrual and follow-up in the manner of a large simple trial.
Year V:
o Patient follow-up in the manner of a large simple trial.
Year VI:
o Patient follow-up in the manner of a large simple trial.
Year VII:
o Patient follow-up in the manner of a large simple trial for six
months.
o Start of the post-trial treatment for six months of placebo patients
with selected treatments from the main phase of the trial (if
necessary, depending on study design). This study after the completion
of the main trial will require additional follow-up of patients in one
or more arms of the trial.
Year VIII
o End of the post-trial treatment for six months of placebo patients
with selected drugs from the main phase of the trial.
o Closeout, data audit, data analysis, and preparation of papers for
publication will occur during this last year.
Additional years may be required depending on the start date, the time
required to complete the pilot studies, and the rate of recruitment for
the main trial.
SPECIAL REQUIREMENTS
The intent of this RFA is to solicit applications from qualified
investigators proposing to serve as Clinical Centers in order to
conduct a large, collaborative randomized double-blind trial testing
neuroprotective agents in patients with early PD. The final study
design will be developed through collaboration between the Oversight
Committee, Coordinating Center, NINDS Scientific Program Director, and
Statistical Center.
-- Special Requirements for Clinical Centers
A Clinical Center is an institution that is actively involved with the
recruitment, evaluation, treatment and follow-up of study participants.
It will consist of a team of researchers with the neurological skills
to apply diagnostic criteria for PD and study selection criteria and to
deliver medical care to PD patients and, optimally, with experience in
collaborative clinical studies. It may have agreements to form a local
network with other nearby institutions to recruit and treat patients
for this study.
A Clinical Center will collaborate with other Clinical Centers and with
the Coordinating Center, Statistical Center, and NINDS Scientific
Program Director, to participate in the development of the pilot study
and trial protocols, to recruit patients to participate in the trial,
and to follow the protocol for each participating patient. Accurate
and complete data reporting are paramount. Complete follow-up in a
large simple trial will require innovative methodology since frequent
patient contact will not be possible. Cooperation with patient
advocacy groups is encouraged as a means for encouraging patient
compliance and commitment to the trial.
A Clinical Center will attempt to identify and recruit all eligible
patients with follow-up of participants according to the final,
approved pilot study and trial protocols using standardized data
collection procedures.
Each Clinical Center is required to recruit two participants per month
during the recruitment phases of the pilot (6 months) and main (36
months) trials. A regional screening/recruitment strategy enlisting the
support of PD advocacy groups may be necessary to achieve this goal at
many sites.
A Clinical Center will participate in the cooperative design of study
protocols and preparation of the manual of operations.
It is critical to the success of this project that each Clinical Center
maintain contact with all recruited patients and carry-out complete,
accurate data collection and timely transmission of the data to the
Coordinating Center. To assure the overall quality of the pilot
studies and trial Clinical Centers must cooperate with data audits and
other quality control procedures established by the protocol, Steering
Committee, and Data and Safety Monitoring Board.
A Clinical Center may participate on the Steering Committee and
Publications Committee, according to the charter of the Steering
Committee.
Each Clinical Center must agree to publish data collected from their
site only in accordance with guidelines established by the Publications
Committee.
Clinical Centers are required to take all appropriate measures to
protect human subjects and ensure adequate representation of genders
and racial/ethnic minorities.
TERMS AND CONDITIONS OF AWARD
The following terms and conditions will be incorporated into the notice
of grant award. The following special terms of award are in addition
to, and not in lieu of, otherwise applicable OMB administrative
guidelines, HHS grant administration regulations at 45 CFR Parts 74 and
92, and other HHS, PHS, and NIH grant administration policies.
1) Collaborative Responsibilities. The administrative and funding
instrument used for this program is a cooperative agreement (U01), an
"assistance" mechanism (rather than an "acquisition" mechanism) in
which substantial NINDS scientific and/or programmatic involvement with
the awardee is anticipated during performance of the activity. Under
the cooperative agreement, the NINDS purpose is to support and/or
stimulate the recipient"s activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is
not to assume direction, prime responsibility, or a dominant role in
the activity. Consistent with this concept, the dominant role and
prime responsibility for the activity resides with the awardee(s) for
the project as a whole, although specific tasks and activities in
carrying out the studies will be shared among the awardees and the
NINDS Program Director and NINDS-appointed Oversight Committee.
The study will be lead by a Steering Committee. Members of this
Committee will include the Principal Investigators of the Coordinating
Center and Statistical Center, and the NINDS Scientific Program
Director. After Clinical Centers are activated, the Principal
Investigators of two Clinical Centers will be chosen by the other three
members and approved by the Oversight Committee. The chair of the
Steering Committee will be the Principal Investigator of the
Coordinating Center. The Steering Committee may appoint subcommittees
to perform specific tasks, one will be a Publication Committee to
establish publication policies and approve publications prior to
submission.
2) Awardees Rights and Responsibilities.
The awardees for the Clinical Centers will:
a) Participate in the design of the study protocols and the writing of
the manual of operations for one or more of the pilot studies and the
large clinical trial,
b) Help develop operational plans and carry out patient recruitment,
treatment, and follow-up that is efficient,
c) Carry out complete and accurate data collection and timely
transmission of the data to the Coordinating Center,
d) Suggest approaches to the analyses of data and participate in
writing manuscripts of the interim and final results of the trial and
pilot studies,
e) Ensure adequate representation of women and racial/ethnic minority
groups in the pilot studies and trial,
f) Willingly adhere to a common study protocol for each pilot study and
the large trial,
g) Take all appropriate measures to protect human subjects, setting a
superior example in this regard for others to follow in the future,
h) Attend all training meetings and annual investigator’s meeting as
outlined in the protocol,
i) If placed on non-recruiting status due to deficiencies in
performance, agree to continue follow-up of participants according to
the protocol unless follow-up arrangements can be made through an
alternate Clinical Center,
j) Agree to publish data collected as part of the trial according to
guidelines established by the Steering/Publications Committee,
k) Carry out the other elements of the research project as described in
this RFA.
Awardees will retain custody of and primary rights to their data
developed under the award, subject to government policies regarding
rights of access. In accordance with the policies and procedures
established by the Steering Committee, all Clinical Center awardees
will be required to provide study data to the Coordinating Center. The
Coordinating Center will, in turn, be required to transmit all data to
the Statistical Center. The data will be stored at the end of the
trial in a format suitable for archival in a United States national
repository at a time when the investigators no longer have a use for
the data. A plan for eventual placement in a national archive will be
developed by the grantees and approved by the NINDS.
3) NINDS Responsibilities. The NINDS will name the Scientific Program
Director for the study. The Program Director’s function will be to
advise the Steering Committee, the Publication Committee, and other
subcommittees in carrying out the trials, including quality control,
interim data and safety monitoring, final data analysis and
interpretation, preparation of publications, and coordination of
efforts of all the project centers. The NINDS Program Director will
have voting membership on the Steering Committee, and as appropriate,
other subcommittees of the Steering Committee including the
Publications Committee. To the extent that the NINDS Scientific
Program Director contributes to the scientific content of the trial,
authorship may be shared in publications with other investigators in
accordance with the same policies of the Publication Committee that
apply to other investigators. A second NINDS Program Scientist will
administer the cooperative agreements and will be responsible for the
fiscal management of the program at the NIH.
Other NINDS scientists may, as appropriate, attend meetings and serve
on study committees and work with awardees on issues coming before the
Steering Committee or its subcommittees. However, in all cases, the
NINDS will have only a single vote on each study committee.
The NINDS will appoint and support the travel and other expenses of a
Data and Safety Monitoring Board, either directly or through a
supplement to the Coordinating Center grant.
The NINDS reserves the right to terminate or curtail the study (or an
individual award) in the event of (a) a major breach in the protocol or
substantial changes in the agreed-upon protocol with which the
Institute does not agree or (b) human subject ethical issues that may
dictate a premature termination or (c) failure to pursue the objectives
stated in this Request for Applications, or (d) substantial shortfall
in recruitment and/or retention of subjects, or (e) a recommendation to
the NINDS by the DSMB to stop a pilot study or the large trial.
4) Governance
An Oversight Committee will be appointed by the NINDS. It will not
include the NINDS Scientific Program Director who is a member of the
Steering Committee or members from the same institution as any Center
in the project. It will include the NINDS Associate Clinical
Directors, an NINDS program scientist with expertise in pre-clinical
research, outside experts in clinical research and Parkinson Disease,
patient advocates and an expert in ethics. Protocols, protocol
modifications, and choice of interventional agents will be reviewed and
approved by the Oversight Committee.
The Steering Committee will comprise the Principal Investigators of the
Coordinating Center and the Statistical Center, the NINDS Scientific
Program Director, and two Principal Investigators from the Clinical
Centers selected by the other members of the Steering Committee and
approved by the Oversight Committee. Initial representation of the
Clinical Centers on the Steering Committee will be based on the
availability of expertise in relevant approaches to study design and
selection of neuroprotective agents. After patient recruitment begins,
membership from the Clinical Centers will rotate and be based on
recruitment and execution. The Steering Committee will have primary
responsibility for developing common clinical protocols and obtaining
approval of the protocols by the NINDS Oversight Committee. They will
also facilitate the conduct and monitoring of the trials, and reporting
the study results. Each member of the Steering Committee will have one
vote, and all major scientific decisions will be determined by majority
vote of the Steering Committee subject to approval by the NINDS
Oversight Committee. The Chair of the Steering Committee will be the
Principal Investigator of the Coordinating Center. The Oversight
Committee must approve all protocol changes. Steering Committee
meetings will most often take place via teleconference call, at least
every six months.
Subcommittees appointed by the Steering Committee and comprised of
Principal Investigators and appropriate staff from the Clinical
Centers, the Coordinating Center, and the Statistical Center will be
involved in the design of the protocols and the manual of operations,
and in ongoing functions of the trials, such as review of ancillary
studies and preparation of publications. Not all Clinical Centers will
necessarily be represented on all subcommittees. The NINDS Program
Director may choose to participate in any of the meetings of these
subcommittees.
The Director, NINDS, will appoint an independent Data and Safety
Monitoring Board, to review periodically the progress of the trials.
It will be comprised of experts in relevant medical, statistical,
operational, and bioethics fields who are not otherwise involved in the
study. The Data and Safety Monitoring Board will oversee participant
safety, approve procedures for blinding, evaluate results, monitor data
quality, and provide operational and policy advice to the NINDS in
accordance with the policies and procedures of the NIH and the NINDS.
The Principal Investigator of the Coordinating Center, the Principal
Investigator of the Statistical Center, and the NINDS Scientific
Program Director may be invited to attend Data and Safety Monitoring
Board meetings. An NINDS representative will be present at all
sessions of the meetings.
5) Arbitration. Any disagreement that may arise in scientific-
programmatic matters between award recipients and NINDS may be brought
to arbitration. An arbitration panel will be composed of three members
- one selected by the Steering Committee (with the NINDS not voting) or
by the individual awardee in the event of an individual disagreement, a
second member selected by NINDS, and a third member selected by the
preceding two members. These special arbitration procedures in no way
affect the awardee’s right to appeal an adverse action that is
otherwise appealable in accordance with the PHS regulations at 42 CFR
Part 50, Subpart D and HHS regulations at 45 CFR Part 16. The
conditions of award will apply and have precedence in all disagreements
unless mutually agreed by both NINDS and the awardee.
MECHANISM OF SUPPORT
The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), an "assistance" mechanism
(rather than an "acquisition" mechanism), in which substantial NIH
scientific and/or programmatic involvement with the awardee is
anticipated during performance of the activity.
The total project period for applications submitted in response to the
present RFA may not exceed five years. The earliest anticipated award
date is July 1, 2002. This is a one time solicitation for
applications. In order to complete the eight-year project to be
proposed in response to this RFA, competitive renewal applications will
be solicited for peer review from the successful applicants four years
after the project starts in order to facilitate continuous funding
beyond five years.
The number of awards to be made and level of support to be provided
depend on receipt of a sufficient number of applications of high
scientific merit. Although this program is provided for in the
financial plans of the National Institute of Neurological Disorders and
Stroke, awards pursuant to this RFA are contingent upon the
availability of funds for this purpose.
FUNDS AVAILABLE
It is expected that approximately $4,321,800 total cost (direct plus
Facilities and Administrative costs) will be available each year over a
five year period for all of the Clinical Centers. It is anticipated
that 42 awards for Clinical Centers will be made for an average over
the entire trial of $73,500 direct costs per year.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, clinics, 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.
INQUIRIES
Written, including electronic mail, and telephone inquiries concerning
this RFA are encouraged. The opportunity to clarify any issues or
questions from potential applicants is welcome.
Direct inquiries regarding scientific or programmatic issues to:
Bernard Ravina, M.D.
Clinical Trial Group
National Institute of Neurological Disorders and Stroke
Neuroscience Center
6001 Executive Blvd.
Rockville, MD 20892
Telephone: (301) 496-9135
FAX (301) 480-1080
Electronic mail: ravinab@ninds.nih.gov
Direct inquiries regarding fiscal matters to:
Gladys Bohler
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd.
Rockville, MD 20892
Telephone: (301) 496-9231
FAX (301) 402-0219
Electronic mail: bohlerg@ninds.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit, by September 15, 2001, a
letter of intent that includes a descriptive title of the proposed
research, name, address, and telephone number of the Principal
Investigator, identities of other key personnel and participating
institutions, and the number and title of the RFA in response to which
the application may be submitted.
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
allows NINDS staff to estimate the potential review workload and to
avoid conflict of interest in the review.
The Letter of Intent is to be sent to:
Scott Janis, PhD
Program Analyst
National Institute of Neurological Disorders and Stroke
Neuroscience Center
Rockville, Maryland 20892
Telephone (301) 496-9135
FAX: (301) 480-1080
email: janiss@ninds.nih.gov
SCHEDULE SUMMARY
Letter of Intent: September 15, 2001
Application Receipt Date: Nov 15, 2001
Scientific Peer Review: Approximately March, 2002
Review by NINDS Advisory Council: May 2002
Earliest Anticipated Award Date: July 1, 2002
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 4/98) is to be used
in applying for these awards. These forms are available at most
institutional offices of sponsored research, from the Grants
Information Office, Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, Suite
6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email:
GrantsInfo@nih.gov.
The RFA label available in the PHS 398 (rev. 4/98) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in delayed processing of the
application such that it may not reach the review committee in time for
review. In addition, the RFA title and number must be typed on line 2a
of the face page of the application form and the YES box must be
marked. The RFA number must be typed on the label as well.
The sample RFA label is available at:
http://grants.nih.gov/grants/funding/phs398/labels.pdf. Please note
this is in pdf format.
Submit a signed, original of the application, including the Checklist,
and three 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 (For express/courier use Bethesda, MD 20817)
At the time of submission, two additional copies of the application
must also be sent to:
Lillian M. Pubols, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center Suite #3208
6001 Executive Blvd.
Bethesda, MD 20892-9529 (For express/courier use Rockville, MD 20852)
Tel.: 301-496-9223
Fax: 301-402-0182
e-mail: LP28E@NIH.GOV
Applications must be received by Nov 15, 2001. 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 announcement 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 a substantial revision of an
application already reviewed, but such an application must follow the
guidance in the PHS Form 398 application instructions for the
preparation of revised applications, including an introduction
addressing the previous critique.
--Special Instructions for Preparing Applications for a Clinical Center
Within the Research Plan portions of the applications for the Clinical
Centers, the following issues should be covered:
o Clinical Centers must be capable of enrolling at least 84
participants in three and a half years for the pilot studies (n=12) and
the main clinical trial (n=72). Applicants should provide
documentation of the availability of PD patients who are early in the
course of their disease, including women and racial/ethnic minorities.
o Applicants should document availability and clinical research
experience of the Clinical Center staff. Additionally, describe the
measures that will be implemented to ensure the safety of study
participants.
o Applicants should describe the clinic environment where the study
visits will be conducted.
o Applicants should document prior involvement (if any) in single-
center and multi-center clinical trials, including experience in
recruiting and following PD patients and patients with other
neurological disorders, and experience in completing data collection
forms in an accurate and timely manner.
o If the Clinical Center will be a consortium of local sites,
applicants should describe the history of the consortium and how it
will operate to ensure uniform patient care and compliance with the
protocol. Additionally, describe the advantages of the collaboration
in terms of cost and recruitment capabilities.
o Clinical Centers must form alliances with PD patient advocates in
their local areas in order to facilitate recruitment and follow-up of
study participants. Applicants should document existing alliances or
describe alliances they intend to establish.
o Applicants should describe their plans for recruiting study
participants, including women and racial/ethnic minorities, retaining
them in the study, and encouraging them to adhere to the protocol.
o Applicants must include an explicit statement of willingness to
cooperate with the other centers in the conduct of one or more clinical
trials testing agents approved by the Oversight and Steering
Committees.
o Clinical Center applicants are encouraged, but not required, to
include creative ideas about study design and discussion of the issues
surrounding neuroprotection trials in PD, as well as to propose and
justify one or more neuroprotective agents for testing.
Please see the Review Considerations.
Budget Instructions for Clinical Centers: The maximal budget is $73,500
direct costs per year for each Clinical Center, to include salary
support for a research nurse coordinator, physician investigator(s)
participation, required travel to training workshops and annual
investigator’s meetings ($1500 per year maximum), and all other
required activities. Receipt of the full award amount is contingent
upon recruitment of 2 participants per month during the 9 month pilot
phase (n=12) and in the three-year main trial recruitment period (n=72)
with successful protocol execution (attempted recruitment of all
eligible patients, timely and complete follow-up and data collection,
adequate protocol adherence, no participant lost-to-follow-up).
Clinical Centers that do not participate in individual protocols or
that do not meet recruitment/execution standards will have the grant
budget reduced. For situations in which applicants have existing
ongoing clinical research in PD, the scientific and budgetary
implications of potential overlap should be described. If a center is
capable of doing excellent research but able to provide fewer or more
patients than requested, then such applications are welcomed. The
requested budgets should be modified in proportion to the proposed
number of patients.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the NINDS. Incomplete or unresponsive
applications will be returned to the applicant without further
consideration.
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 NINDS in accordance with the review
criteria stated below. 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 will be discussed, assigned a priority score, and receive a
second level review by the National Institute of Neurological Disorders
and Stroke Advisory Council.
Review Criteria
Applications will be judged on the basis of the ability of the
investigators to fulfill the SPECIAL REQUIREMENTS for each component
described in this RFA, comply with the cooperative agreement terms and
conditions of award, and to attain the goals stated above in the
RESEARCH OBJECTIVE section as demonstrated by the capability and
expertise documented in the application.
The specific review criteria are described below.
The final design for the clinical trial will be developed
collaboratively by the Steering Committee relying largely on the
expertise of the Coordinating Center and the Statistical Center. The
major role of the Clinical Centers is to recruit patients. The peer
review group will therefore focus on evidence that the Clinical Center
applicant can recruit sufficient patients and willingly accept the
responsibility to meet or exceed all requirements for human subject
protection.
Recruitment Capability: Is there evidence of prior experience in the
recruitment of Parkinson patients to clinical trials? Are there
realistic plans for the recruitment of patients, including women and
minority participants for the proposed clinical trial? Does the
application provide credible estimates of recruitment capability
supported by detailed data derived from the current population of
Parkinson patients that demonstrate all of the characteristics required
by the trial selection criteria (clinical diagnosis of PD, recent
diagnosis soon after first symptoms develop, not taking drugs that
induce Parkinsonism, absence of other disease likely to prevent 5-year
follow-up. Patients may be recently started on dopaminergic
treatment). Is there sufficient evidence based on prior experience in
clinical trials, chart reviews, and from other documents that the
center will be likely to recruit sufficient patients? If patient
availability is limited at the primary institution, are there
satisfactory agreements with other institutions or clinics in the same
geographic area? If the recruitment plans include more than two
clinical sites at one Clinical Center are adequate measures proposed to
ensure uniform patient care and compliance with the protocol? Does the
Clinical Center have evidence of the percentage of eligible Parkinson
patients who have agreed to participate in previous trials? Are the
advantages of collaboration in terms of cost and recruitment
capabilities (including the recruitment of minorities and women)
clearly described? Is the organizational/administrative plan for such
arrangements clearly delineated and efficient?
Retention Capabilities: Are there complete plans and/or experience in
achieving high rates of follow-up of trial participants and promoting
high levels of adherence to the protocol?
Environment: Does the environment in which the work will be done
contribute to the probability of success?
In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:
The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will
also be evaluated.
The reasonableness of the proposed budget and duration in relation to
the proposed research.
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.
The adequacy of the proposed plan to share data, if appropriate.
AWARD CRITERIA
It is anticipated that the earliest award date will be July 1, 2002.
Applications recommended by the National Institute of Neurological
Disorders and Stroke Advisory Council will be considered for award
based upon (a) scientific and technical merit, (b) program balance, and
(c) availability of funds.
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 sub-populations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification are 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 research involving human subjects should
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities
as Subjects in Clinical Research," published in the NIH Guide for
Grants and Contracts on August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a
complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:
The revisions relate to NIH defined Phase III clinical trials and
require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual,
and to conduct and report analyses, as appropriate, by sex/gender
and/or racial/ethnic group differences.
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://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators also may obtain copies of these policies from the program
staff listed under INQUIRIES. Program staff may also provide additional
relevant information concerning the policy.
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. Reviewers are cautioned that
their anonymity may be compromised when they directly access an
Internet site.
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:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm
Applicants may wish to place data collected under this RFA 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
this award.
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 Request for
Applications (RFA), Parkinson Disease Neuroprotection Clinical Trial:
Clinical Centers , is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople/.
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance
No. 93.853. 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 and Federal Regulations 42 CFR
52 and 45 CFR Parts 74 and 92. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products. In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a
facility) in which regular or routine education, library, day care,
health care, or early childhood development services are provided to
children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.
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