PARKINSON DISEASE NEUROPROTECTION CLINICAL TRIAL:  COORDINATING AND 
STATISTICAL CENTERS

Release Date:  February 27, 2001
 
RFA:  RFA-NS-01-012

National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  March 30, 2001
Application Receipt Date:       May 15, 2001

PURPOSE

The Neurodegeneration and Clinical Trial Groups of the National 
Institute of Neurological Disorders and Stroke (NINDS) request 
applications for 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.  Two 
types of applications are requested:  for (1) a Coordinating Center, 
and (2) a Statistical Center.  Applications for multiple Clinical 
Centers will be sought in a separate solicitation.  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 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 
replacing 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 rate 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 
pharmacological agents to slow the progression of PD.

With many potential neuroprotective interventions available, sequential 
testing of single agents is not the optimal approach to expeditiously 
reducing disability from PD.  Clinical trial designs in which several 
agents are compared to a single control group have the advantages of 
participant acceptance because 1) assignment to control is less likely 
and 2) because of  potential to compare directly the active 
interventions.  Factorial designs in which some participants may 
receive more than one active intervention offer the potential to assess 
effects of combinations of neuroprotective agents that may work by 
different mechanisms, although statistical power to define interactions 
may be limited.  Large, simple clinical trials focus on limited goals 
and a few key outcomes, facilitating participation of large numbers of 
investigators; 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 
such 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 relatively early after diagnosis who have 
at least two of the four cardinal signs.
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.

At present, available biomarkers have not been adequately validated as 
correlating with clinically relevant neuroprotection to substitute for 
clinical outcomes in the large phase III clinical trial.  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 are 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 
the U.S. citizens with PD.

Studies that test simultaneously multiple agents can be more efficient 
than a series of trials testing a single agent, making use of a single 
control group and allowing comparison of agents and combinations of 
agents. A major intent of this RFA is to encourage active involvement 
of the Statistical Center in all phases of the clinical trial 
development, contributing creative input for statistical design and 
trial management.  New designs and methodologies not previously applied 
to neurodegenerative disease are sought.

Specific design issues relevant to neuroprotection trials in PD require 
careful consideration, with potential solutions incorporated into trial 
design:
1. Unequal use of other symptomatic PD treatments during the course of 
the trial that may modify progression (i.e. the putative neurotoxicity 
of levodopa).
2. Occult symptomatic effects that may confound assessment of 
neuroprotection.
3. Selection of optimal outcome measures, particularly functional and 
disability scales appropriate for early PD patients followed for a mean 
of 3-4 years.
4. Testing of multiple agents in parallel and/or factorial designs.

Innovative approaches to these design issues are required. 

Sample size requirements for testing individual agents will vary 
according to the estimated minimum clinically important benefit 
associated with individual agents, the choice of outcome measures and 
their anticipated change during the planned period of observation (a 
mean of four years) of up to 3024 participants.  

Soliciting putative neuroprotective agents for testing will be from 
several sources and is likely to identify numerous agents linked to and 
justified by hypothesized mechanisms of neurodegeneration in PD, but 
other methods for identifying potential agents will also be considered. 
These will not be limited to compounds already approved by the US Food 
and Drug Administration.  Pharmaceutical companies may have 
investigational treatments that are potential neuroprotectants, but 
that are not being developed for PD for reasons unrelated to their 
potential efficacy. Agents proposed by the successful applicants, 
biomedical research companies, pharmaceutical companies, research 
scientists, and patients/PD advocates will be solicited and considered. 
Final selection of agents will be made by the NINDS-appointed Oversight 
Committee in collaboration with the Coordinating Center, the 
Statistical Center and advice from experts in the field.  

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 protecting human subjects.  
These will be solicited through a separate RFA.

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, evaluate and approve all 
protocol changes during the course of the trial.
2. The Data Safety Monitoring Board will monitor study execution and 
safety issues, 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, 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, as 
well as 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.
  
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 clinical trial will be ongoing for 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 the Coordinating Center or the 
Statistical Center 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 -- The Coordinating Center

The Coordinating Center will develop (with the Statistical Center and 
NINDS Scientific Program Director), implement and manage the study 
protocols and manuals of operation for the pilot and full-scale 
multicenter trials, provide overall leadership for the Clinical Centers 
during recruitment and follow-up, collect, store, and maintain data 
from the Clinical Centers, and assure quality control and blinded 
monitoring of data. Ongoing monitoring of performance of the Clinical 
Centers will be done. The Coordinating Center will work cooperatively 
with Clinical Centers, a separate Statistical Center, and the NINDS 
staff. Design and generation of data forms, data entry systems and 
intra-component communications systems will be undertaken by the 
Coordinating Center in collaboration with the statistical center. 

The staff of the Coordinating Center will be required to travel to 
meetings during the planning phases for development of the study 
designs, protocols, study manuals of operations, and data forms.  It 
will manage the logistics of all committee activities during the pilot 
and main trials and will produce minutes of these meetings.  In 
addition to proposing and organizing the meetings required for 
collaboration between the components, the Coordinating Center will be 
expected to maintain close communication with the NINDS Scientific 
Program Director, each Clinical Center, cooperating patient advocacy 
groups, and the Statistical Center.  

The Coordinating Center will be responsible for developing procedures 
to assure that all participants provide appropriate consent prior to 
participation in any aspect of the study, to assure compliance with 
federal regulations at each study site, to adhere to NINDS, FDA and (if 
appropriate) pharmaceutical company procedures for adverse event 
reporting.  

The Coordinating Center will recommend two or more potential 
neuroprotectant agents for testing, accompanied by thorough 
justification of each agent (ultimate choice of the specific agents and 
number of treatment arms will be made by the Oversight Committee in 
collaboration with the Coordinating and Statistical Centers after the 
grants are awarded). Applicants are encouraged to contact 
pharmaceutical manufacturers of agents proposed for the trial to 
determine their interest in participating in protocol development and 
to provide both drug and placebo for testing in the trial.  An estimate 
of the risks expected from the prolonged use of any proposed agents 
should be provided, if known.  In addition, the investigators should 
discuss acceptable risks for neuroprotective treatments for Parkinson 
disease.  Applicants are requested to determine the level of interest 
of these manufacturers in participating in the trials to be conducted, 
including providing drug to the investigators.  The results of these 
discussions should be clearly described in the grant application. If a 
pharmaceutical company wishes information to be collected that is not 
necessary for the scientific conduct of the trial, the cost of this 
additional information is to be borne by the company and the data is to 
be gathered in such a way that does not threaten the blinding or 
execution of the trial.

The Coordinating Center will propose criteria for selecting two or more 
neuroprotective agents from those likely to be elicited in response to 
this RFA (i.e. in addition to those agents proposed in the Coordinating 
Center application).  These criteria should consider anticipated 
magnitude of benefit, toxicity, strength of preclinical evidence 
(including biomarkers) suggesting benefit.  

Applications for the Coordinating Center should address key design 
issues pertinent to demonstrating clinical proof of neuroprotection 
(i.e. “what constitutes convincing clinical evidence of 
neuroprotection?”  This is not meant to imply that agents that have 
symptomatic effect could not also be neuroprotectants.)  
Inclusion/exclusion criteria and recruitment strategies should be 
included in the application that are consistent with the overall 
research objective of this RFA. Outcome measures relevant to 
neuroprotection trials should be proposed and their rate of 
change/event rate estimated. A general plan and budget for drug 
distribution to the Clinical Centers should also be included.  Plans 
for assuring protocol adherence and complete follow-up of all study 
participants, including early identification of problem Clinical 
Centers, should be part of the application.

Plans for central adjudication of eligibility and outcomes (including 
adverse events) and an appropriate budget for adjudicators (consulting 
costs, telecommunication, travel) is the responsibility of the Clinical 
Coordinating Center.  Training for investigators from the Clinical 
Centers will be provided by the Coordinating Center.

-- Special Requirements -- The Statistical Center

The Statistical Center will have an important role in all aspects of 
the project, offering creative approaches to study design, execution, 
and ongoing monitoring  and analysis. This includes proposals for 
distinguishing neuroprotective vs. symptomatic effects and options for 
innovative study designs that will permit the maximum number of agents 
to be tested, considering potential interactions, balancing magnitude 
of treatment effects with a maximal total sample size of about 3024 
participants.  Proposals for specific trial design await selection of 
the specific agents to be tested, but demonstration of capability and 
innovative approaches to design of trials with multiple agents and long 
follow-up periods is crucial to the application.

It is the intent of this RFA that the Statistical Center be 
operationally independent of the Coordinating Center, in order to 
stimulate creative interactions, to facilitate maintaining the blind, 
and to offer independent assessment of the ongoing trial performance 
and data quality.  

The Statistical Center will work with the Coordinating Center to 
develop the study protocols for the pilot and main trials (for approval 
by the Oversight Committee) and procedures for monitoring quality 
control and participant safety.  It will ensure consistency of the 
final data forms with the protocols and assure that the final forms 
contain all data necessary to perform appropriate analysis of the trial 
and pilot studies.  It will perform tests of the consistency of the 
data.  It will prepare periodic reports for the DSMB (performing the 
required interim analyses). It will prepare interim reports for the 
Coordinating Center on performance of the Clinical Centers, including 
recruitment, patient safety, and data quality.  It will perform all 
analyses for publication of trial data and prepare archival records of 
the trial.

The Statistical Center will arrange central adjudication of outcomes 
relating to efficacy and safety (as required by the final study 
protocol).  The Statistical Center will develop procedures for and 
monitoring of blinding of administration of the study interventions. 

The staff of the Statistical Center will be required to travel to 
meetings during the planning phases and to participate on the Steering 
Committee and other subcommittees. As a general rule, each individual 
Principal Investigator will be responsible for allowing important 
breakthroughs resulting from this work to become available to the 
clinical community through the literature, through preparation and 
submission of manuscripts and abstracts to appropriate journals in a 
timely fashion.

TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the notice 
of grant award, which is provided to the Principal Investigator and the 
Institutional Official. 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 the NIH Grants Policy 
Statement.

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, 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 Subcommittee to establish 
publication policies and approve publications prior to submission.

2) Awardees’ Rights and Responsibilities. 

Coordinating Center

The awardees for the Coordinating Center will:

a) In conjunction with the Clinical Centers, the Statistical Center, 
and NINDS, lead the development of the trial designs and manuals of 
operation.
b) Collect, store, and evaluate the quality of the data transmitted by 
the Clinical Centers.
c) Monitor performance of Clinical Centers in implementing the 
protocols
d) Transmit the study database to the Statistical Center on a regular 
basis.
e) Manage meetings of the Steering Committee.
f) Attend blinded portions of the PSMB as requested
g) Ensure that recruitment of patients proceeds on schedule
h) Provide training for the clinical coordinators and investigators at 
the clinical centers.
i) Recommend neuroprotectants for inclusion in the project.
j) Provide a system for drug distribution.
k) Make all required safety reports and provide an in-house safety 
monitor to review safety data and assist the Statistical Center in 
preparation of reports to the DSMB.
l) The Coordinating Center will coordinate, through a Publications 
Committee, the preparation and publication of scientific results of the 
pilot and main studies.  In order to protect the integrity of the 
trial, the Coordinating Center will assure that no public or scientific 
presentations of the results of a pilot trial or the main trial are 
made until the primary report for the trial has been accepted for 
publication (there will be no exception to this rule unless recommended 
by the DSMB to protect participants or for public safety).  
m) Carry out the other elements of the research project as described in 
this RFA.

The awardees for the Statistical Center will:
a) Participate extensively in the design of each pilot study and the 
large simple clinical trial.  This includes development and 
characterization of outcome measures.
b) Develop efficient and innovative statistical approaches to the pilot 
studies and large simple trial performed by this collaboration.  
Encourage a creative approach on the part of the Coordinating Center 
and Clinical Centers.
c) Act to reduce bias and protect any blinding during the entire 
project.
d) Provide interim reports on the progress of the Clinical Centers, 
including reports on recruitment and data quality
e) Provide analyses and reports for the Steering Committee, Data and 
Safety Monitoring Board, and the National Institute of Neurological 
Disorders and Stroke.
f) Conduct analyses of the data from the pilot studies and the large 
trial for publication in peer-reviewed scientific journals.
g) Anticipate and participate in the solution of problems with 
recruitment at participating centers.
h) Provide a copy of the final study database for archival.
i) Carry out 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 
assist 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 study committees, either of the 
whole or on subcommittees. 

The NINDS will appoint and support the travel and other expenses of a 
Data Safety and 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 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.  All protocol 
changes must be approved by the Oversight Committee. 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, the NINDS Program Director may 
be invited to attend Data and Safety Monitoring Board meetings, but 
will not attend unblinded sessions of those 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.  Under the cooperative 
agreement, the NIH 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. 
Details of the responsibilities, relationships and governance of the 
study to be funded under cooperative agreements are discussed later in 
this document under the section "Terms and Conditions of Award."

The modular grant mechanism will not apply for either of the two 
different types of applications.

The total project period for applications submitted in response to the 
present RFA may not exceed five years.  The anticipated award date is 
September 30, 2001.  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 $1,470,000 total cost (direct plus 
Facilities and Administrative costs) will be available each year over a 
five year period for the Coordinating and Statistical Centers.  It is 
anticipated that one award for the Coordinating Center will be made for 
approximately $800,000 direct cost per year, and one award for $250,000 
direct cost per year for a Statistical Center. Later, in response to a 
separate RFA it is anticipated that 42 awards for Clinical Centers will 
be made.

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.

It is the intent of the RFA that the Statistical Center and the 
Coordinating Center be functionally independent in order to preserve 
blinding and to solicit independent reports on the performance of the 
Coordinating Center from the Statistical Center, and vise-versa, for 
the Oversight Committee.  

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:

Scott Janis, Ph.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:  janiss@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 March 30, 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 
plan 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:                  March 30, 2001
Application Receipt Date:          May 15, 2001
Scientific Peer Review:            Approximately August 1, 2001
Review by NINDS Advisory Council:  September 13-14, 2001
Anticipated Award Date:            September 30, 2001

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 301-435-0714, 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/label-bk.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 May 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 -- Coordinating 
Center

The Research Plan of applications for the Coordinating Center may 
exceed the usual 25 page limit, but should not exceed 35 pages.  Data 
collection forms, sample consent forms, and other key elements of a 
manual of operations may be included in an appendix for reference.

Within the Research Plan of the applications for the Coordinating 
Center, the following issues should be addressed:

o Applicants should present their recommendation and justification for 
selection of two or more agents to slow or stop the progression of 
Parkinson Disease.  In addition they should discuss the availability of 
the agents recommended and the necessity for doing pilot studies.  
Applicants should propose primary and secondary outcomes for randomized 
clinical trials of drug therapy to slow or stop the progression of 
Parkinson disease.  It is anticipated that the pilot studies and large 
simple clinical trial will be conducted among a broad group of 
Parkinson patients recently diagnosed or recently started on and 
responsive to dopaminergic therapy.  Experience in data management, 
including development of data collection instruments and database 
management and integrity should be described.  Applicants should 
propose study designs for any necessary pilot studies and a subsequent 
large simple trial to be conducted over the course of this project.  
Solutions should be suggested for potential problems related to the 
design and conduct of such trials.  The applicant’s study design should 
propose methodology that limits the amount of information collected on 
each patient, but maximizes accuracy and reliability of the information 
that is collected.  This methodology should include efficient 
mechanisms for ensuring patient compliance and long term participation 
in the study.  In addition, selection criteria should be specified 
which include a broad spectrum of Parkinson disease and that will not 
impede rapid recruitment of a large number of patients.  Applicants 
should provide a justification for the subject selection criteria, and 
the projected time necessary for recruitment.  Applicants must propose 
primary and secondary outcomes.  The primary outcome must be a reliable 
test of patient function or disability.  A proposal for evaluating 
different candidate treatments in order to select a specific drug for 
the proposed trial should be provided. 

o In cases where applicants have an existing clinical research program 
in PD ongoing, the scientific and economic implications of any overlap 
should be outlined in the application.

o The Coordinating Center application should explain how the proposed 
center will relate with other components in this collaborative project.  
As the study protocols will require extensive collaboration between the 
Statistical Center, and Steering Committee, applicants should 
demonstrate the ability to work effectively with interdependent groups 
to provide input on all aspects of study design and execution.

o Since this research proposes a phase III clinical trial, careful 
attention must be paid to the policies described below in the section 
entitled “INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN 
SUBJECTS.”

o Budget Instructions for Coordinating Center:

The five-year budget in the application for the Coordinating Center 
should provide for expertise in Parkinson disease and leadership of a 
major multicenter clinical trial.

For ease of review and administration, it is requested that the 
Coordinating Center budget contain a separate budget page for data 
management.

Salary: Enter the dollar amounts for each position for which funds are 
requested for all staff in each Center. 

Computer and Data Management support should be included in the 
Coordinating Center budget.  It should also include a clinical 
coordinator responsible for training of Clinical Center coordinators 
and facilitating the flow of data; and the administrative support 
necessary for the communication required for leading a large 
collaborative clinical trial; and staffing for ensuring patient safety, 
medical review of possible adverse events, and reviewing compliance 
with selection criteria.  

Salary limitation on grants and cooperative agreements and contracts 
can be accessed at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-013.html.

Consultant costs:  Provide the names and organizational affiliations of 
all consultants whether or not funds are requested.  Include the 
anticipated duration of consultation and the expected rate of 
compensation, travel, per diem, and other related costs.

Equipment/Supplies/Other Expense: List each item of equipment 
separately.  Itemize supply categories for amounts above $1000. Itemize 
Other Expenses by category and unit cost.

Allowance should be made for drug distribution, but not the cost of 
purchasing drug or placebo; drug distribution, but not the cost of 
purchasing drug or placebo.

Travel: Include travel to organizational meetings, Steering Committee 
meetings and other meetings, and site visits for quality control. For 
planning, assume that all study meetings that involve more than one 
center would occur in Bethesda, Maryland.  Monthly travel to meetings 
in Bethesda, Maryland, for the first 3 months of the trial, and 
quarterly thereafter should be planned  (alternate meeting schedules 
can be proposed).  

Consortium/Contractual Costs:  If there is a need for consortium 
activity, submit a separate detailed initial budget and projected 
budget for the proposed project period for each participating 
consortium/contractual organization. 

--Special Instructions for Preparing Applications -- Statistical Center

Within the Research Plan portions of the applications for the 
Statistical Center, the following issues should be covered:

o A proposal for a design for a clinical trial of 2 to 6 different 
drugs to prevent or stop the progression of Parkinson’s disease.  
Possible alternative designs should also be discussed.  The number of 
different drugs to be tested will be limited by the total sample size 
of 3024.  The application should propose how the Statistical Center 
could participate in the drug selection process.  The specific trial 
design awaits selection of the agents to be tested and of outcome 
measures and their change during observation, but demonstration of 
capability and innovative approaches to the design and execution of 
neuroprotection trials in PD is crucial to the application.

o The Statistical Center application should explain how the proposed 
center will relate with other components in this collaborative project.  
As the study protocols will require extensive collaboration between the 
Statistical Center and the Coordinating Center and Steering Committee, 
applicants should demonstrate the ability to work effectively with 
clinicians to provide input on all aspects of study design and 
execution.

o Specific plans should be presented for monitoring of data quality.

o A major emphasis should be placed on the demonstration of the 
capability to develop new trial designs to address the special 
challenges presented by clinical trials for neuroprotectants for 
Parkinson’s disease that are described above.

o The application should demonstrate that the statistical center has 
appropriate expertise in the design and analysis of phase I and phase 
II clinical trials.  

o Plans for generating the randomization codes and collaboration with 
the drug distribution center.

o Since this research proposes a phase III clinical trial, careful 
attention must be paid to the policies described below in the section 
entitled “INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN 
SUBJECTS.”

o Budget Instructions for Coordinating Center:  The five-year budget in 
the application for the statistical center will focus on support for 
statistical expertise and data analysis for the main trial and any 
pilot studies.  The costs of basic data collection and quality control 
should not be included in the Statistical Center budget since these 
activities will occur in the Coordinating Center.  However, resources 
to check for completeness and consistency of key data elements should 
be included in the Statistical Center budget. 

Salary: Enter the dollar amounts for each position for which funds are 
requested for all staff in each Center. 

Salary limitation on grants and cooperative agreements and contracts 
can be accessed at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-013.html.

Consultant costs:  Provide the names and organizational affiliations of 
all consultants whether or not funds are requested.  Include the 
anticipated duration of consultation and the expected rate of 
compensation, travel, per diem, and other related costs.

Equipment/Supplies/Other Expense: List each item of equipment 
separately.  Itemize supply categories for amounts above $1000. Itemize 
Other Expenses by category and unit cost.

The costs of preparing multiple publications for peer review should be 
planned for in the Statistical Center budget, including the reporting 
of results from any pilot phase I/II studies.  

Travel: Monthly travel to meetings in Bethesda, Maryland, for the first 
3 months of the trial, and quarterly thereafter should be planned.

Consortium/Contractual Costs:  If there is a need for consortium 
activity , submit a separate detailed initial budget and projected 
budget for the proposed project period for each participating 
consortium/contractual organization. 

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: DUTIES AND 
RESPONSIBILITES 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 demonstrated in the 
application.  

The specific review criteria for each component are described below.

-- Review Criteria for Coordinating Center

The structure of the collaborative group described in this RFA is 
intended to promote the development of new clinical trial methodology 
by the interaction between the Statistical Center and the Coordinating 
Center.  Therefore, the review criteria for the Coordinating Center 
emphasize knowledge of Parkinson disease, clinical scales, clinical 
protocol design, data management, safety monitoring.  Expertise in 
statistical design and analysis is expected to reside in the 
independent Statistical Center.  

Review of applications for the Coordinating Center will be based on the 
following criteria:

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

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

- Approach: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of 
the project? Does the applicant acknowledge potential problem areas and 
consider alternative tactics? Demonstrable knowledge of the potential 
problems associated with the conduct of clinical trials of drug therapy 
to treat neurodegenerative disease and approaches to their solution 
will be evaluated.

Data Management: Adequacy of the proposed plans and experience relating 
to data collection, management, editing, processing, quality control, 
and transmission to the Statistical Center for further checking of 
consistency and accuracy will be evaluated.

- Investigators:  Are the investigators appropriately trained and well-
suited to carry out this work?  Is the work proposed appropriate to the 
experience level of the Principal Investigator and other researchers? 
Do the professional, technical, and administrative staff have 
documented competence and relevant experience specifically pertinent to 
the operation of a Coordinating Center for a large simple randomized 
clinical trial of drug therapy to prevent progression of Parkinson 
Disease?  Do they have prior experience collecting data from multiple 
clinical sites, monitoring the data quality and blinded monitoring of 
patient safety?  Do the proposed Coordinating Center personnel have 
experience in protecting trial blinding and utilizing procedures to 
insure the safety and confidentiality of all records?

Experience in working with drug packaging and distribution centers: 
Because the trial will involve multiple treatments, it is anticipated 
that a central distribution center may be required to furnish both drug 
and placebo in a timely fashion to the Clinical Centers.  The 
applicants' experience in establishing and working cooperatively with a 
Drug Distribution Center in cooperative studies will be evaluated.

- Resources and Environment: Does the scientific environment in which 
the work will be done contribute to the probability of success? Do the 
proposed experiments take advantage of unique features of the 
scientific environment or employ useful collaborative arrangements? Is 
there evidence of institutional support? Reviewers will evaluate the 
adequacy of the proposed facility, technical hardware, and space and 
the appropriateness of the organizational and administrative structure 
of the proposed Clinical Coordinating Center.

- Collaboration:  Do the investigators demonstrate willingness to work 
cooperatively with the investigators in other centers participating in 
the project.  Adequacy of the approach to developing a cooperative 
relationship among the participating Statistical Center and the 
Clinical Centers and exercising appropriate leadership in matters of 
study design, data acquisition, data management, data quality, and data 
analysis.  Evidence of experience in and willingness to participate 
appropriately in a collaborative study as described in this RFA.

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  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.

o  The reasonableness of the proposed budget and duration in relation 
to the proposed research.

o  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.

-- Review Criteria for Statistical Center

The structure of the collaborative group described in this RFA is 
intended to promote the development of new clinical trial methodology 
by the interaction between the Statistical Center and the Coordinating 
Center.  Therefore, the review criteria for the Statistical Center 
emphasize innovative statistical approaches to the evaluation of 
treatments of neurodegenerative diseases such as PD.  Expertise in PD 
and other neurodegenerative diseases expected to reside in the 
Coordinating Center.  

Review of applications for the Statistical Center will be based on the 
following specific criteria:

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

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

- Investigators:  Are the investigators appropriately trained and well-
suited to carry out this work?  Is the work proposed appropriate to the 
experience level of the Principal Investigator and other researchers?

Competence:  Has the application documented specific competence and 
relevant experience of professional, technical, and administrative 
staff pertinent to the design and analysis of a large simple randomized 
clinical trial of multiple drug therapies to prevent progression of 
Parkinson Disease and any necessary phase I or phase II pilot studies?  
Do the proposed investigators demonstrate the capability to design 
phase I and phase II studies that are innovative and practical?  Is it 
likely that the proposed Statistical Center will be able to lead the 
application of cutting-edge statistical research to the proposed pilot 
studies and the main large simple trial?

Collaboration:  Do the investigators demonstrate willingness to work 
cooperatively with the investigators in other centers participating in 
the studies?  Have the investigators demonstrated the capability to 
communicate effectively with clinicians in the collaborative 
development of protocols?  While collaborating with clinical 
researchers will the Statistical Center investigators demonstrate 
flexibility and creative adaptability to specific clinical questions 
rather than procrustean application of conventional methods?

- Resources and Environment: Does the scientific environment in which 
the work will be done contribute to the probability of success? Do the 
proposed experiments take advantage of unique features of the 
scientific environment or employ useful collaborative arrangements? Is 
there evidence of institutional support? Reviewers will evaluate the 
adequacy of the proposed facility, technical hardware, and space and 
the appropriateness of the organizational and administrative structure 
of the proposed Statistical Center. 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  

o  The reasonableness of the proposed budget and duration in relation 
to the proposed research.

o  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. In particular, reviewers will 
evaluate whether confidentiality will be protected adequately by the 
proposed Statistical Center.

AWARD CRITERIA

It is anticipated that awards will be made on September 30, 2001.  
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.

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: 
Coordinating and Statistical 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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