PARKINSON DISEASE NEUROPROTECTION CLINICAL TRIAL: CLINICAL CENTERS
 
RELEASE DATE:  September 2, 2004
 
RFA Number:  RFA-NS-05-004  

EXPIRATION DATE:  January 25, 2005

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:  
National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.853
 
LETTER OF INTENT RECEIPT DATE:  December 23, 2004
APPLICATION RECEIPT DATE:  January 24, 2005  
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

The Neurodegeneration and Clinical Trial Groups of the National 
Institute of Neurological Disorders and Stroke (NINDS) request 
applications for additional clinical centers to collaborate in clinical 
trials to test potential neuroprotective agents in Parkinson’s disease 
(PD). These studies, the neuroprotection exploratory trials in PD (NET-
PD) include pilot clinical trials and plans for a large, simple phase 
III clinical trial. Previous solicitations were issued for the clinical 
and statistical coordinating centers 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-01-012.html)
and clinical centers 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-02-010.html.
Pilot clinical trials are ongoing with over forty 
participating sites.  The agents under study currently include 
creatine, minocycline, Coenzyme Q10, and a neuroimmunophilin ligand.  
These pilot studies are expected to complete follow-up in the 3rd 
quarter of 2005. Depending upon the results of these studies a phase 
III trial with one of these agents may be conducted or additional pilot 
studies of different agents may be performed. Sites are sought to join 
NET-PD to participate in these future studies.
 
RESEARCH OBJECTIVES

The ultimate objective is to demonstrate efficacy in a randomized, 
double-blind clinical trial of one or more pharmacological agents for 
slowing the progression of PD and to determine the safety and 
tolerability of these agents.

BACKGROUND

Parkinson’s disease (PD) affects nearly a million Americans, a number 
that will increase over the coming decades with an annual incidence of 
up to 50,000.  While available medical therapies are usually effective 
for controlling symptoms for the early 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.  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 “preclinical” phase 
of uncertain duration preceding diagnosis, during which loss of these 
dopaminergic neurons progresses until the threshold for clinical 
symptoms is reached, estimated to be about 60-70%% 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.  Despite the substantial 
disability due to PD, few interventional studies have evaluated agents 
that might slow disease progression. Effective clinical neuroprotection 
would 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.

Currently there are two ongoing pilot studies: one parallel study of 
creatine (10mg/day) and minocycline (200mg/ day), and a second parallel 
study of Coenzyme Q10 (2400mg/day) and a neuroimmunophilin ligand, GPI 
1485 (4000mg/day). These pilot clinical trials will determine if these 
agents warrant further study in a phase III trial. This phase III trial 
would be conducted in the manner of a large, simple trial, with a focus 
on clinically meaningful endpoints and relatively infrequent follow-up 
visits.  The exact study design depends upon the agents selected and 
outcome information from the pilot studies. In the event that all pilot 
trials are negative, additional agents may be tested in further pilot 
trials.  The trials are being conducted at over 40 centers in the 
United States with the Clinical Coordinating Center at the University 
of Rochester and the Statistical Coordinating Center at the Medical 
University of South Carolina.
 
Neuroprotection clinical trials were initially called for in the 
Parkinson Agenda for the NIH which 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.

Design of a clinical neuroprotection trial.

Final design of future clinical trials will result from collaboration 
between and consensus of the NET-PD steering committee and the NINDS 
Oversight Committee (see Study Organization, below).  Key elements of 
the phase III trial will include the following:

1)  Inclusion of PD patients early after clinical diagnosis with two or 
more of the four cardinal signs, not taking drugs that induce 
Parkinsonism, absence of other disease likely to prevent long term 
follow-up.  
2)  Design capable of detection of “small” but clinically meaningful 
treatment effects.
3)  General design of the phase III study as a “large, simple” trial, 
including large sample size (up to 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)  Ongoing pilot studies to develop dose and safety information, to 
select pharmaceutical agents that merit phase III evaluation, and to 
refine outcome measures (years I-III of the program). These studies 
will be complete when new sites are added to NET-PD.
2)  Selection of additional agents for pilot studies as needed.
3)  Main multi-arm trial (approximately 6 years, or more).
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 initiative may last up to nine years, 
or more. 

Participants in the trial will be enrolled in the early stages of the 
disease, 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 of 3 or more years, 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 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 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 have emerged from 
the previous RFAs for this trial.  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 will 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 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 ongoing (and 
potentially future pilot studies) may be needed.  Pilot trials will 
determine dose, safety, assess the presence of a dopaminergic effect, 
and refine outcome measures.  These pilot studies will be critical to 
the eventual success of any subsequent large, definitive, phase III 
trial.  

STUDY ORGANIZATION

The organizational structure currently in place for these studies 
consists of the following components:

1.  The Coordinating Center will develop and manage the protocol (in 
conjunction with the steering committee and Oversight committee), 
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 will recruit and follow participants, emphasizing 
participant adherence and the highest standards of protocol execution.  
Three representatives of Clinical Centers will be selected to 
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 is organized by NINDS and includes NINDS 
clinical directors and program directors with expertise in pre-clinical 
science of neuroprotection and in clinical trials, together with 
extramural experts in PD and neurodegeneration, statistics, ethics, and 
representatives of PD advocacy groups.  The Oversight Committee will 
give final approval to the agents to be tested, approve the final study 
design and plans for analysis developed by collaboration between the 
Steering committee. The oversight board may also evaluate and approve 
major protocol changes during the course of the trial in conjunction 
with the Data and Safety Monitoring Board (see below).  The oversight 
board is composed of outside experts and NIH staff, who constitute 
approximately 25% of the members. 

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). This board will also evaluate and give final approval to 
any study modifications.
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 three selected members drawn from the Clinical Centers.  
The Steering Committee will approve the 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 scientific Program Director will function 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 at least one large simple randomized, placebo-
controlled clinical trial will be completed during the period of this 
initiative, although this depends on the results of the pilot trials.  
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 
and timing of protocols implemented may vary depending upon the 
specific study designs agreed upon. 

Years I-III (will be completed prior to the addition of new sites):  

o Drug selection, protocol development, recruitment, and follow-up for 
the first two pilot studies.

Year IV: 

o Protocol development for the large-scale clinical trial will be 
ongoing and completed within 6 months of completion of the pilot 
trials.  The manual of operations will be produced by the Coordinating 
Center in cooperation with the Statistical Center and Steering 
Committee.

o Patient accrual will begin and continue for up to 30 months (or more) 
at an average rate of two patients per month per center.

Year V:   

o Patient accrual and follow-up in the manner of a large simple trial.

Year VI:   

o Patient accrual and 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, the rate of recruitment for the 
main trial, and the follow-up period needed.  Should additional years 
be necessary, applicants will be required to submit a competitive 
renewal application.  

MECHANISM OF SUPPORT 

This RFA will use a NIH cooperative (U10) award mechanism.  As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  This RFA is a one-time solicitation.  
The anticipated award date is September, 2005. 

This RFA uses just-in-time concepts and the non-modular budgeting 
formats
http://grants.nih.gov/grants/funding/modular/modular.htm).  

The NIH (U10) is a cooperative agreement award mechanism in which the 
Principal Investigator retains the primary responsibility and dominant 
role for planning, directing, and executing the proposed project, with 
NIH staff being substantially involved as a partner with the Principal 
Investigator, as described under the section "Cooperative Agreement 
Terms and Conditions of Award." 

FUNDS AVAILABLE 
 
The number of centers funded under this solicitation is subject to the 
availability of funds at the time of award.  NINDS may commit up to 
$1,200,000 in FY 2005 to fund as many as 12 new grants in response to 
this RFA, but may select a smaller number of centers based on the needs 
of the study, quality of applications, and availability of funds.  An 
applicant may request a project period of up to 5 years and a budget 
for direct costs of up to $ 73,500 per year.  Because the nature and 
scope of the proposed research will vary from study to study, funds 
will be awarded based on expected recruitment and performance and 
future awards will be based on demonstrated recruitment and 
performance, measured on a per subject basis. It is anticipated, 
therefore, that the size and duration of each award will also vary from 
center to center. 

ELIGIBLE INSTITUTIONS 
 
You may submit (an) application(s) if your institution has any of the 
following characteristics:
   
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations.
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.   

SPECIAL REQUIREMENTS

The intent of this RFA is to solicit applications from qualified 
investigators proposing to serve as Clinical Centers in order to 
conduct pilot trials and 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 
Steering Committee and Oversight Committees. 

Special Requirements for Clinical Centers 

1) 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.

2) 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.

3) 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. 

4) Each Clinical Center is currently required to recruit one 
participant per month during the for the pilot trials when de novo 
subjects are sought and it is expected that this will increase to two 
or more subjects per month during the main trial when the study 
population may be broadened to include patients on symptomatic 
therapies. A regional screening/recruitment strategy enlisting the 
support of PD advocacy groups may be necessary to achieve this goal at 
many sites. 

5) A Clinical Center will participate in the cooperative design of 
study protocols and preparation of the manual of operations.

6) 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.

7) A Clinical Center may participate on the Steering Committee and 
Publications Committee, according to the charter of the Steering 
Committee.

8) Each Clinical Center must agree to publish data collected from their 
site only in accordance with guidelines established by the Publications 
Committee.

9) Clinical Centers are required to take all appropriate measures to 
protect human subjects and ensure adequate representation of genders 
and racial/ethnic minorities. 

COOPERATIVE AGREEMENT 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.

The administrative and funding instrument used for this program is a 
cooperative agreement (U10), 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 Scientific Program Director 
and NINDS-appointed Oversight Committee as described below.  

1) 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 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 
subjects in the pilot studies and phase III clinical 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 as required 
by DHHS regulations and NIH policy; 
h) Attend all training meetings and annual investigators’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.

2) NINDS Responsibilities.  The NINDS will assign a Scientific Program 
Director for the study, who will have substantial programmatic 
involvement that is above and beyond the normal programmatic 
stewardship, as described below.

The Scientific Program Director’s function is 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 Scientific Program Director has 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 Director/Official administers the cooperative 
agreements and will be responsible for the normal programmatic and 
fiscal management and stewardship 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 has appointed and directly supports the travel and other 
expenses of a Data and Safety Monitoring Board.

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.

3) Governance

An Oversight Committee has been appointed by the NINDS.  It does not 
include the NINDS Scientific Program Director who is a member of the 
Steering Committee.  It includes the NINDS Associate Clinical Directors 
for Clinical Trials, an NINDS program scientist with expertise in pre-
clinical research, outside experts in clinical research and statistics 
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.  
Approximately 25% of the oversight board are NIH staff.    

The study will be governed by a Steering Committee. The Steering 
Committee is comprised of the Principal Investigators of the 
Coordinating Center and the Statistical Center, the NINDS Scientific 
Program Director, and three 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 may rotate. 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 Steering Committee has primary responsibility for developing common 
clinical protocols and obtaining approval of the protocols by the NINDS 
Oversight Committee.  They also facilitate the conduct and monitoring 
of the trials, and reporting the study results.  

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. Subcommittees 
appointed by the Steering Committee and consisting 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 Scientific 
Program Director may choose to participate in any of the meetings of 
these subcommittees.

The Director, NINDS, has appointed an independent Data and Safety 
Monitoring Board, to review periodically the progress of the trials.  
It is 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.

4) 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.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

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 inquires regarding peer review matters to:

Katherine Woodbury-Harris, 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) 496-5980
Fax: 301-402-0182
Electronic mail:  harrisk@ninds.nih.gov

Direct inquiries regarding fiscal matters to:

Aaron Kinchen
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd.
Rockville, MD  20892
Telephone:  (301) 496-7386
FAX (301) 402-0219
Electronic mail:  kinchena@ninds.nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, the information 
that it contains allows IC staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to:

Scott Janis, PhD
Clinical Research Program Manager
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

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms.  Applications must have a DUN and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The D&B number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The D&B 
number should be entered on line 11 of the face page of the PHS 398 
form. The PHS 398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.
Telecommunications for the disabled: TTY 301-451-0088
 
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/labels.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
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
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and 
all copies of the appendix material must be sent to:

Katherine Woodbury-Harris, 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) 496-5980
Fax: 301-402-0182
harrisk@ninds.nih.gov

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 2 PD patients 
per month, including newly diagnosed patients not requiring medication 
and patients recently on medication for PD.  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.  

APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review. 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and 
funding assignment within 8 weeks.
 
The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW 
application.  That is, the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text 
must not be marked to indicate the changes from the previous unfunded 
version of the application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NINDS. Incomplete and/or nonresponsive 
applications will not be reviewed.  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 NINDS in 
accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will:

o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications 
under review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Advisory Neurological 
Disorders And Stroke 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 newly diagnosed patients and 
those early in the course of treated PD, 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.

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of 
human subjects and protections from research risk relating to their 
participation in the proposed research will be assessed. (See criteria 
included in the section on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy 
of plans to include subjects from both genders, all racial and ethnic 
groups (and subgroups), and children as appropriate for the scientific 
goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the 
sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals 
are to be used in the project, the five items described under Section f 
of the PHS 398 research grant application instructions (rev. 5/2001) 
will be assessed.  

ADDITIONAL REVIEW CONSIDERATIONS

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

SHARING RESEARCH DATA: It is expected that data will be submitted in a 
timely fashion to the coordination center. Additional data sharing may 
occur as part of this multi-center collaboration. Investigators 
submitting an NIH application seeking $500,000 or more in direct costs 
in any single year are expected to include a plan for data sharing or 
state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing  This requirement will 
apply for all applications received in response to this RFA, even 
though the direct costs requested will be less than the $500,000 
threshold.  Investigators should seek guidance from their institutions, 
on issues related to institutional policies, local IRB rules, as well 
as local, state and Federal laws and regulations, including the Privacy 
Rule. Reviewers will consider the data sharing plan but will not factor 
the plan into the determination of the scientific merit or the priority 
score.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  December 23, 2004
Application Receipt Date:  January 24, 2005
Peer Review Date:  April, 2005
Council Review:  May, 2005
Earliest Anticipated Start Date:  September 2005

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities 
involving live, vertebrate animals must comply with PHS Policy on 
Humane Care and Use of Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), 
as mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the 
USDA Animal Welfare Regulations 
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated 
with reference to the risks to the subjects, the adequacy of protection 
against these risks, the potential benefits of the research to the 
subjects and others, and the importance of the knowledge gained or to 
be gained.  http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required 
for all types of clinical trials, including physiologic, toxicity, and 
dose-finding studies (phase I); efficacy studies (phase II); efficacy, 
effectiveness and comparative trials (phase III).  The establishment of 
data and safety monitoring boards (DSMBs) is required for multi-site 
clinical trials involving interventions that entail potential risk to 
the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide 
for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA: Investigators submitting an NIH application 
seeking $500,000 or more in direct costs in any single year are 
expected to include a plan for data sharing or state why this is not 
possible. http://grants.nih.gov/grants/policy/data_sharing  
Investigators should seek guidance from their institutions, on issues 
related to institutional policies, local IRB rules, as well as local, 
state and Federal laws and regulations, including the Privacy Rule. 
Reviewers will consider the data sharing plan but will not factor the 
plan into the determination of the scientific merit or the priority 
score.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy 
of the NIH that women and members of minority groups and their sub-
populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating that inclusion is inappropriate with respect to the health of 
the subjects or the purpose of the research. This policy results from 
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS:  The NIH maintains a policy that children (i.e., individuals 
under the age of 21) must be included in all human subjects research, 
conducted or supported by the NIH, unless there are scientific and 
ethical reasons not to include them. 

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the inclusion of children as 
participants in research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  
NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  
The Department of Health and Human Services (DHHS) issued final 
modification to the “Standards for Privacy of Individually Identifiable 
Health Information”, the “Privacy Rule,” on August 14, 2002.  The 
Privacy Rule is a federal regulation under the Health Insurance 
Portability and Accountability Act (HIPAA) of 1996 that governs the 
protection of individually identifiable health information, and is 
administered and enforced by the DHHS Office for Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule 
reside with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, 
including a complete Regulation Text and a set of decision tools on “Am 
I a covered entity?”  Information on the impact of the HIPAA Privacy 
Rule on NIH processes involving the review, funding, and progress 
monitoring of grants, cooperative agreements, and research contracts 
can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 
proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in an NIH solicitation, Internet 
addresses (URLs) should not be used to provide information necessary to 
the review because reviewers are under no obligation to view the 
Internet sites.   Furthermore, we caution reviewers that their anonymity 
may be compromised when they directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas. This RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284and under Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92. All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at http://grants.nih.gov/grants/policy/policy.htm

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products.  In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits 
smoking in certain facilities (or in some cases, any portion of a 
facility) in which regular or routine education, library, day care, 
health care, or early childhood development services are provided to 
children.  This is consistent with the PHS mission to protect and 
advance the physical and mental health of the American people.

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NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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