PARKINSON DISEASE NEUROPROTECTION CLINICAL TRIAL:  CLINICAL CENTERS

Release Date:  July 2, 2001

RFA:  RFA-NS-02-010

National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  September 15, 2001
Application Receipt Date:       Nov 15, 2001

PURPOSE

The Neurodegeneration and Clinical Trial Groups of the National 
Institute of Neurological Disorders and Stroke (NINDS) request 
applications for clinical centers to collaborate in the performance of 
a large, double-blind randomized trial of two or more potential 
neuroprotective agents in patients early in the course of Parkinson’s 
disease.  Applications for coordinating and statistical centers were 
requested in a separate solicitation 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-01-012.html).  The 
trial was called for in the NIH Parkinson Research Agenda 
(http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm).  The 
neuroprotectants to be tested in the trial have not yet been chosen and 
will be selected by an NINDS-appointed Oversight Committee from among 
those proposed by the applicants who respond to this Request for 
Applications (RFA) as well as from those suggested by others, including 
NINDS grantees, pharmaceutical companies, patients, and patient 
advocates.

BACKGROUND

Parkinson’s disease (PD) affects nearly a million Americans, a number 
that will increase over the coming decades.  While available medical 
therapies are usually effective for controlling symptoms for the 
initial years following diagnosis, higher doses of multiple agents are 
required over time, with increasing side-effects and incomplete control 
of symptoms. While these treatments can dramatically improve the lives 
of patients with Parkinson’s disease initially, they have been based on 
dopamine replacement since the early 1970’s.  They do not address the 
underlying disease cause or the currently inevitable biological 
progression of PD.  The typical course of PD is one of gradual 
worsening over a decade or more, corresponding to ongoing neuronal loss 
affecting cells in the pigmented nuclei of the brain, particularly in 
the substantia nigra.  There is a long “preclinical” phase preceding 
diagnosis, during which loss of these dopaminergic neurons progresses 
until the threshold for clinical symptoms is reached, estimated to be 
about 70-80% loss by the time of diagnosis.  Given this prolonged 
course of progressive neuronal loss, strategies aimed at reducing the 
rates of neuronal loss or dysfunction (i.e. clinical neuroprotection or 
disease-modification) are particularly important in this disorder.  
Effective clinical neuroprotection would importantly reduce PD-related 
disability for hundreds of thousands of Americans, prompting the 
National Institute of Neurological Disorders and Stroke (NINDS) to 
invite qualified investigators to submit grant applications for 
components of a clinical trial aimed at identifying agents to slow the 
progression of PD.

With many potential neuroprotective interventions available, clinical 
trial designs in which several agents are compared to a single control 
group have many advantages that may increase participant acceptance 
because 1) assignment to control is less likely and 2) there is the 
potential to compare directly the active interventions.  Factorial 
designs in which some participants may receive more than one active 
intervention offer the further potential to assess effects of 
combinations of neuroprotective agents that may work by different 
mechanisms, (although statistical power to define interactions may be 
limited).  By definition, large, simple clinical trials focus on 
limited goals and a few key outcomes supplementing such streamlined 
protocols, subsets of participants in large, simple trials at selected 
sites can be more intensively investigated.

Despite the substantial disability due to PD, few interventional 
studies have evaluated agents that might retard disease progression. A 
previous investigator-initiated trial supported by NINDS, Deprenyl and 
Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), evaluated 
selegiline (Deprenyl) and vitamin E as treatments for PD.  Vitamin E 
was found ineffective, and selegiline has not become widely used 
because of uncertainty about a neuroprotective vs. symptomatic effect 
due to an initially unsuspected dopa-agonist action.

The Parkinson Agenda for the NIH was published in April, 2000 
(http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm). The 
agenda calls for the initiation of randomized controlled clinical 
trials to test potential neuroprotectants.   Expert advice regarding 
implementation of this initiative was solicited at the meeting 
“Therapeutic Initiatives in Parkinson Disease” convened by the NINDS 
(13-Oct-00, Bethesda), which included representatives of several NIH 
Institutes and national experts in PD and clinical research in 
neurodegenerative disorders.

RESEARCH OBJECTIVE

To demonstrate convincingly in a randomized, double-blind clinical 
trial the efficacy of one or more pharmacological agents for slowing 
progression of PD and to determine the toxicity and tolerability of 
these agents.

Design of a clinical neuroprotection trial.

Final design of the clinical trial will result from collaboration 
between and consensus of the Coordinating Center, NINDS scientific 
staff, the Statistical Center, Principal Investigators from Clinical 
Centers, and the NINDS Oversight Committee (see Study Organization, 
below).  It is anticipated that key elements of the trial will include 
the following:
1)  Inclusion of PD patients early after clinical diagnosis with two of 
the four cardinal signs, not taking drugs that induce Parkinsonism, 
absence of other disease likely to prevent 5-year follow-up.  Patients 
have recently started dopaminergic treatment.
2)  Design capable of detection of small treatment effects because of 
the clinical importance of even modest benefits to PD patients.
3)  General design as a “large, simple” trial, including large sample 
size (about 3000 participants), infrequent regular follow-up, and 
limited data collection, focusing on functional and disability-related 
outcomes, including those that can be assessed without direct patient 
contact using either mail or telephone.
4)  Prospective plans to distinguish neuroprotective effects from 
occult symptomatic benefits.

The trial will involve the following phases:
1)  Selection of potential neuroprotective agents.
2)  Pilot studies to develop dose and safety information, to select 
pharmaceutical agents useful for the main trial, and to refine outcome 
measures (approximately one year).
3)  Main multi-arm trial (approximately 6 years).
4)  If necessary, post-trial administration of one or more apparently 
efficacious neuroprotective agents to all participants to assess occult 
symptomatic effects and convincingly establish neuroprotection  (six 
months to one year).

The entire trial may last up to eight years. 

Participants in the trial will be enrolled in the earliest stages of 
the disease possible, and may or may not require symptomatic therapies 
(depending on the final approved study design). Based on observations 
from the initial and second randomization in the DATATOP trial, it is 
anticipated that there will be measurable evidence of disease 
progression during follow-up averaging three to four years (extending 
to five years in some participants), both in those receiving 
dopaminergic agents and those who are not. Outcome instrument 
development and/or adaptation of existing instruments for use with a 
large, simple trial design is a key objective of the pilot phase. Use 
of disability and functional outcome scales sensitive to changes seen 
during the early course of PD will be emphasized as the primary 
outcomes. Effects on non-motor features will be included.

Available biomarkers have not been appropriately validated to 
substitute for clinical outcomes in the large phase III.  Assessment of 
biomarkers for screening and in selection of neuroprotective agents 
will be considered.  Since biomarkers as surrogate outcomes require 
validation by correlation with clinical outcomes in “positive” clinical 
trials, the concomitant assessment of biomarkers in the large 
neuroprotection trial, particularly at selected centers or patient 
subsets, will also be considered, balancing expense and complexity with 
the overall goals of the large trial. 

Several candidate agents for neuroprotection testing will likely emerge 
from this RFA.  Because even a small neuroprotective effect with a 
minimally toxic agent would be important to detect, a relatively large 
trial is required.  Minimizing the cost for each participant will 
permit larger numbers of participants and make it possible to evaluate 
more potential neuroprotective agents.  The boundary presented by large 
sample sizes and the cost of conventional studies needs to be crossed 
in order to obtain the initial success required to sustain research of 
further neuroprotective treatments.  Detecting small effects requires 
large sample sizes, but it does not mandate a complex protocol.  
Rather, intermediate contact by mail or telephone, allowing less 
frequent clinical contact, may provide the needed data at many time 
points, and reduce costs.  It is anticipated that highly reliable 
functional outcome or disability scales that are multi-modal can be 
included to simplify outcome measures and reduce the cost of the trial.

Several design issues common to large, simple trials must be considered 
and addressed.  Compliance is a major concern, particularly if one or 
more of the treatments being tested is generally available either over-
the-counter or through prescription.  Dropouts and patients lost to 
follow-up must be minimized.  Inexpensive methods to maintain patient 
loyalty and protocol adherence between infrequent clinic visits will be 
important for successful execution. Reliable outcome measures assessed 
by different clinicians and other medical professionals are necessary, 
since primary care providers may have more ready access to a patient 
than the neurologist.  It may also be helpful to enlist the support of 
PD patient advocacy groups to help build and maintain patient loyalty.

Rapid recruitment and initiation of treatment are essential, 
facilitated by limited inclusion/exclusion criteria.  Limited exclusion 
criteria will expose a broad spectrum of PD patients to the selected 
neuroprotective drugs, a likely advantage in the initial clinical 
trials. (When the characteristics that predict a patient’s response to 
a particular drug are not known, the chances of detecting any effect 
increase if there is a wide spectrum of PD patients participating in 
the study.)  If neuroprotective effects are detected, further studies 
may then define appropriate selection criteria. Participants will 
reflect the gender and racial/ethnic composition of U.S. citizens with 
PD.

Pilot data to determine the maximum safe dose for PD patients is not 
likely to be available for all agents to be tested, and a pilot study 
may be needed for most agents.  Pilot trials should determine dose, 
safety, assess the presence of a dopaminergic effect, and refine/test 
outcome measures.  These pilot studies may be critical to the eventual 
success of the subsequent large, definitive trial.  Consequently, an 
initial pilot phase for testing each of the agents will be available as 
part of the planning phase for the trial.

STUDY ORGANIZATION

The organizational structure will consist of the following components:

1.  The Coordinating Center will develop and manage the protocol, 
assure compliance with regulations, supervise and encourage 
recruitment, collect, store, and maintain data from clinical centers 
including recruitment and dropout data, prepare blinded reports on 
adverse events, monitor study execution at clinical sites, and supply 
study medications to each site.  The principal investigator of the 
Coordinating Center will serve as chair of the Steering Committee.  The 
Coordinating Center will be blinded to treatment group during 
recruitment and follow-up in all trials.  
2.  The Statistical Center will be involved in study design, in 
planning and performing analysis, and prepare all summary reports to 
the Coordinating Center, Oversight Committee and NINDS-appointed Data 
and Safety Monitoring Board (DSMB).
3.  Clinical Centers (initially 42 sites) will recruit and follow 
participants, emphasizing participant adherence and the highest 
standards of protocol execution.  Representatives of Clinical Centers 
will selectively participate on the Steering Committee. During the 
trial, Clinical Centers may be added, deactivated, or placed in a 
follow-up mode with budget reduction, depending on performance and 
recruitment requirements and requirements for protecting human 
subjects.

In addition, there will be three key committees:

1.  The Oversight Committee will be organized by the NINDS and include 
NINDS clinical directors and program directors with expertise in 
preclinical science of neuroprotection and in clinical trials, together 
with extramural experts in PD and neurodegeneration and with 
representatives of PD advocacy groups.  The Oversight Committee will 
give final approval to the agents to be tested, approve the final study 
protocol and plans for analysis developed by collaboration between the 
Coordinating Center and Statistical Center, and evaluate and approve 
all protocol changes during the course of the trial.
2.  The Data and Safety Monitoring Board will monitor study execution 
and safety issues, and propose and consider interim analyses.  It will 
be appointed by the NINDS and include a non-voting NINDS representative 
who will act independently of the NINDS Scientific Program Director 
(see below).
3.  The Steering Committee will consist of the Coordinating Center 
principal investigator (who will chair the committee), the Principal 
Investigator of the Statistical Center, the NINDS Scientific Program 
Director, and selected members drawn from the Clinical Centers.  The 
specific membership and charter of the Steering Committee will be 
proposed by the Coordinating Center and approved by the Oversight 
Committee.  The Steering Committee will approve the final protocols, 
supervise overall execution of the trial, generate and approve study 
policies, consider modifications of the protocol and operations, and 
plan and draft study-related publications.

The NINDS will name a Program Director whose function will be to 
expedite the activities outlined under Terms and Conditions (below), 
and serve as representative for the NINDS to the trial components.  The 
NINDS Program Director will participate on the scientific committees of 
the trial, but she/he will not be responsible for fiscal management of 
the cooperative agreement, which will be done by a second NINDS program 
scientist.

STUDY TIMETABLE 

It is anticipated that one large simple randomized, placebo-controlled 
clinical trial will be completed during the 8 year period of this 
initiative.  In addition, one or more pilot studies may be done for 
each of the proposed therapeutic agents to determine safety, dose, and 
feasibility parameters.  Although the tentative timetable below 
indicates that multiple simultaneous pilot studies succeeded by one 
large simple clinical trial of multiple agents will be performed, the 
actual number of protocols implemented may vary depending upon the 
specific study designs agreed upon. 

Year I:  

o Protocol development for pilot studies (3 months).

o Patient recruitment and follow-up for several simultaneous pilot 
studies (6 to 9 months).  Up to 12 patients per Clinical Center (n=42) 
will be recruited (total 504).

o Protocol development for the large-scale clinical trial will be 
ongoing for an entire year and completed with a full manual of 
operations during the last three months of the first year.  The manual 
of operations will be produced by the Coordinating Center in 
cooperation with the Statistical Center.

Year II: 

o Patient accrual will begin at 42 centers and continue for 36 months 
at an average rate of two patients per month per center (total = 3024 
participants).

Year III:   

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

Year IV:   

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

Year V:

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

Year VI:

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

Year VII:

o Patient follow-up in the manner of a large simple trial for six 
months.
o Start of the post-trial treatment for six months of placebo patients 
with selected treatments from the main phase of the trial (if 
necessary, depending on study design).  This study after the completion 
of the main trial will require additional follow-up of patients in one 
or more arms of the trial.

Year VIII

o End of the post-trial treatment for six months of placebo patients 
with selected drugs from the main phase of the trial.

o Closeout, data audit, data analysis, and preparation of papers for 
publication will occur during this last year.

Additional years may be required depending on the start date, the time 
required to complete the pilot studies, and the rate of recruitment for 
the main trial.

SPECIAL REQUIREMENTS

The intent of this RFA is to solicit applications from qualified 
investigators proposing to serve as Clinical Centers in order to 
conduct a large, collaborative randomized double-blind trial testing 
neuroprotective agents in patients with early PD.  The final study 
design will be developed through collaboration between the Oversight 
Committee, Coordinating Center, NINDS Scientific Program Director, and 
Statistical Center.

-- Special Requirements for Clinical Centers

A Clinical Center is an institution that is actively involved with the 
recruitment, evaluation, treatment and follow-up of study participants.  
It will consist of a team of researchers with the neurological skills 
to apply diagnostic criteria for PD and study selection criteria and to 
deliver medical care to PD patients and, optimally, with experience in 
collaborative clinical studies.  It may have agreements to form a local 
network with other nearby institutions to recruit and treat patients 
for this study.

A Clinical Center will collaborate with other Clinical Centers and with 
the Coordinating Center, Statistical Center, and NINDS Scientific 
Program Director, to participate in the development of the pilot study 
and trial protocols, to recruit patients to participate in the trial, 
and to follow the protocol for each participating patient.  Accurate 
and complete data reporting are paramount.  Complete follow-up in a 
large simple trial will require innovative methodology since frequent 
patient contact will not be possible.  Cooperation with patient 
advocacy groups is encouraged as a means for encouraging patient 
compliance and commitment to the trial.

A Clinical Center will attempt to identify and recruit all eligible 
patients with follow-up of participants according to the final, 
approved pilot study and trial protocols using standardized data 
collection procedures. 

Each Clinical Center is required to recruit two participants per month 
during the recruitment phases of the pilot (6 months) and main (36 
months) trials. A regional screening/recruitment strategy enlisting the 
support of PD advocacy groups may be necessary to achieve this goal at 
many sites. 

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

It is critical to the success of this project that each Clinical Center 
maintain contact with all recruited patients and carry-out complete, 
accurate data collection and timely transmission of the data to the 
Coordinating Center.  To assure the overall quality of the pilot 
studies and trial Clinical Centers must cooperate with data audits and 
other quality control procedures established by the protocol, Steering 
Committee, and Data and Safety Monitoring Board.

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

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

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

TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the notice 
of grant award.  The following special terms of award are in addition 
to, and not in lieu of, otherwise applicable OMB administrative 
guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 
92, and other HHS, PHS, and NIH grant administration policies.

1) Collaborative Responsibilities.  The administrative and funding 
instrument used for this program is a cooperative agreement (U01), an 
"assistance" mechanism (rather than an "acquisition" mechanism) in 
which substantial NINDS scientific and/or programmatic involvement with 
the awardee is anticipated during performance of the activity.  Under 
the cooperative agreement, the NINDS purpose is to support and/or 
stimulate the recipient"s activity by involvement in and otherwise 
working jointly with the award recipient in a partner role, but it is 
not to assume direction, prime responsibility, or a dominant role in 
the activity.  Consistent with this concept, the dominant role and 
prime responsibility for the activity resides with the awardee(s) for 
the project as a whole, although specific tasks and activities in 
carrying out the studies will be shared among the awardees and the 
NINDS Program Director and NINDS-appointed Oversight Committee.  

The study will be lead by a Steering Committee.  Members of this 
Committee will include the Principal Investigators of the Coordinating 
Center and Statistical Center, and the NINDS Scientific Program 
Director.  After Clinical Centers are activated, the Principal 
Investigators of two Clinical Centers will be chosen by the other three 
members and approved by the Oversight Committee.  The chair of the 
Steering Committee will be the Principal Investigator of the 
Coordinating Center.  The Steering Committee may appoint subcommittees 
to perform specific tasks, one will be a Publication Committee to 
establish publication policies and approve publications prior to 
submission.

2) Awardees’ Rights and Responsibilities. 

The awardees for the Clinical Centers will:

a) Participate in the design of the study protocols and the writing of 
the manual of operations for one or more of the pilot studies and the 
large clinical trial,
b) Help develop operational plans and carry out patient recruitment, 
treatment, and follow-up that is efficient,
c) Carry out complete and accurate data collection and timely 
transmission of the data to the Coordinating Center,
d) Suggest approaches to the analyses of data and participate in 
writing manuscripts of the interim and final results of the trial and 
pilot studies,
e) Ensure adequate representation of women and racial/ethnic minority 
groups in the pilot studies and trial,
f) Willingly adhere to a common study protocol for each pilot study and 
the large trial,
g) Take all appropriate measures to protect human subjects, setting a 
superior example in this regard for others to follow in the future,
h) Attend all training meetings and annual investigator’s meeting as 
outlined in the protocol,
i) If placed on non-recruiting status due to deficiencies in 
performance, agree to continue follow-up of participants according to 
the protocol unless follow-up arrangements can be made through an 
alternate Clinical Center,
j) Agree to publish data collected as part of the trial according to 
guidelines established by the Steering/Publications Committee,
k) Carry out the other elements of the research project as described in 
this RFA.

Awardees will retain custody of and primary rights to their data 
developed under the award, subject to government policies regarding 
rights of access.  In accordance with the policies and procedures 
established by the Steering Committee, all Clinical Center awardees 
will be required to provide study data to the Coordinating Center.  The 
Coordinating Center will, in turn, be required to transmit all data to 
the Statistical Center.  The data will be stored at the end of the 
trial in a format suitable for archival in a United States national 
repository at a time when the investigators no longer have a use for 
the data.  A plan for eventual placement in a national archive will be 
developed by the grantees and approved by the NINDS.

3) NINDS Responsibilities.  The NINDS will name the Scientific Program 
Director for the study.  The Program Director’s function will be to 
advise the Steering Committee, the Publication Committee, and other 
subcommittees in carrying out the trials, including quality control, 
interim data and safety monitoring, final data analysis and 
interpretation, preparation of publications, and coordination of 
efforts of all the project centers.  The NINDS Program Director will 
have voting membership on the Steering Committee, and as appropriate, 
other subcommittees of the Steering Committee including the 
Publications Committee.  To the extent that the NINDS Scientific 
Program Director contributes to the scientific content of the trial, 
authorship may be shared in publications with other investigators in 
accordance with the same policies of the Publication Committee that 
apply to other investigators.  A second NINDS Program Scientist will 
administer the cooperative agreements and will be responsible for the 
fiscal management of the program at the NIH.

Other NINDS scientists may, as appropriate, attend meetings and serve 
on study committees and work with awardees on issues coming before the 
Steering Committee or its subcommittees.  However, in all cases, the 
NINDS will have only a single vote on each study committee. 

The NINDS will appoint and support the travel and other expenses of a 
Data and Safety Monitoring Board, either directly or through a 
supplement to the Coordinating Center grant.

The NINDS reserves the right to terminate or curtail the study (or an 
individual award) in the event of (a) a major breach in the protocol or 
substantial changes in the agreed-upon protocol with which the 
Institute does not agree or (b) human subject ethical issues that may 
dictate a premature termination or (c) failure to pursue the objectives 
stated in this Request for Applications, or (d) substantial shortfall 
in recruitment and/or retention of subjects, or (e) a recommendation to 
the NINDS by the DSMB to stop a pilot study or the large trial.

4) Governance

An Oversight Committee will be appointed by the NINDS.  It will not 
include the NINDS Scientific Program Director who is a member of the 
Steering Committee or members from the same institution as any Center 
in the project.  It will include the NINDS Associate Clinical 
Directors, an NINDS program scientist with expertise in pre-clinical 
research, outside experts in clinical research and Parkinson Disease, 
patient advocates and an expert in ethics.  Protocols, protocol 
modifications, and choice of interventional agents will be reviewed and 
approved by the Oversight Committee.  

The Steering Committee will comprise the Principal Investigators of the 
Coordinating Center and the Statistical Center, the NINDS Scientific 
Program Director, and two Principal Investigators from the Clinical 
Centers selected by the other members of the Steering Committee and 
approved by the Oversight Committee.  Initial representation of the 
Clinical Centers on the Steering Committee will be based on the 
availability of expertise in relevant approaches to study design and 
selection of neuroprotective agents.  After patient recruitment begins, 
membership from the Clinical Centers will rotate and be based on 
recruitment and execution.  The Steering Committee will have primary 
responsibility for developing common clinical protocols and obtaining 
approval of the protocols by the NINDS Oversight Committee.  They will 
also facilitate the conduct and monitoring of the trials, and reporting 
the study results.  Each member of the Steering Committee will have one 
vote, and all major scientific decisions will be determined by majority 
vote of the Steering Committee subject to approval by the NINDS 
Oversight Committee.  The Chair of the Steering Committee will be the 
Principal Investigator of the Coordinating Center.  The Oversight 
Committee must approve all protocol changes.  Steering Committee 
meetings will most often take place via teleconference call, at least 
every six months.

Subcommittees appointed by the Steering Committee and comprised of 
Principal Investigators and appropriate staff from the Clinical 
Centers, the Coordinating Center, and the Statistical Center will be 
involved in the design of the protocols and the manual of operations, 
and in ongoing functions of the trials, such as review of ancillary 
studies and preparation of publications.  Not all Clinical Centers will 
necessarily be represented on all subcommittees.  The NINDS Program 
Director may choose to participate in any of the meetings of these 
subcommittees.

The Director, NINDS, will appoint an independent Data and Safety 
Monitoring Board, to review periodically the progress of the trials.  
It will be comprised of experts in relevant medical, statistical, 
operational, and bioethics fields who are not otherwise involved in the 
study.  The Data and Safety Monitoring Board will oversee participant 
safety, approve procedures for blinding, evaluate results, monitor data 
quality, and provide operational and policy advice to the NINDS in 
accordance with the policies and procedures of the NIH and the NINDS.  
The Principal Investigator of the Coordinating Center, the Principal 
Investigator of the Statistical Center, and the NINDS Scientific 
Program Director may be invited to attend Data and Safety Monitoring 
Board meetings.  An NINDS representative will be present at all 
sessions of the meetings.

5) Arbitration.  Any disagreement that may arise in scientific-
programmatic matters between award recipients and NINDS may be brought 
to arbitration.  An arbitration panel will be composed of three members 
- one selected by the Steering Committee (with the NINDS not voting) or 
by the individual awardee in the event of an individual disagreement, a 
second member selected by NINDS, and a third member selected by the 
preceding two members.  These special arbitration procedures in no way 
affect the awardee’s right to appeal an adverse action that is 
otherwise appealable in accordance with the PHS regulations at 42 CFR 
Part 50, Subpart D and HHS regulations at 45 CFR Part 16.  The 
conditions of award will apply and have precedence in all disagreements 
unless mutually agreed by both NINDS and the awardee.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program 
will be a cooperative agreement (U01), an "assistance" mechanism 
(rather than an "acquisition" mechanism), in which substantial NIH 
scientific and/or programmatic involvement with the awardee is 
anticipated during performance of the activity.  

The total project period for applications submitted in response to the 
present RFA may not exceed five years.  The earliest anticipated award 
date is July 1, 2002.  This is a one time solicitation for 
applications.  In order to complete the eight-year project to be 
proposed in response to this RFA, competitive renewal applications will 
be solicited for peer review from the successful applicants four years 
after the project starts in order to facilitate continuous funding 
beyond five years.

The number of awards to be made and level of support to be provided 
depend on receipt of a sufficient number of applications of high 
scientific merit.  Although this program is provided for in the 
financial plans of the National Institute of Neurological Disorders and 
Stroke, awards pursuant to this RFA are contingent upon the 
availability of funds for this purpose.

FUNDS AVAILABLE

It is expected that approximately $4,321,800 total cost (direct plus 
Facilities and Administrative costs) will be available each year over a 
five year period for all of the Clinical Centers.  It is anticipated 
that 42 awards for Clinical Centers will be made for an average over 
the entire trial of $73,500 direct costs per year.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and 
non-profit organizations, public and private, such as universities, 
colleges, hospitals, clinics, laboratories, units of State and Local 
governments, and eligible agencies of the Federal Government.  
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as principal investigators.

INQUIRIES

Written, including electronic mail, and telephone inquiries concerning 
this RFA are encouraged.  The opportunity to clarify any issues or 
questions from potential applicants is welcome.

Direct inquiries regarding scientific or programmatic issues to:

Bernard Ravina, M.D.
Clinical Trial Group
National Institute of Neurological Disorders and Stroke
Neuroscience Center
6001 Executive Blvd.
Rockville, MD  20892
Telephone:  (301) 496-9135
FAX (301) 480-1080
Electronic mail:  ravinab@ninds.nih.gov

Direct inquiries regarding fiscal matters to:

Gladys Bohler
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd.
Rockville, MD  20892
Telephone:  (301) 496-9231
FAX (301) 402-0219
Electronic mail:  bohlerg@ninds.nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit, by September 15, 2001, a 
letter of intent that includes a descriptive title of the proposed 
research, name, address, and telephone number of the Principal 
Investigator, identities of other key personnel and participating 
institutions, and the number and title of the RFA in response to which 
the application may be submitted.

Although a letter of intent is not required, is not binding, and does 
not enter into the review of subsequent applications, the information 
allows NINDS staff to estimate the potential review workload and to 
avoid conflict of interest in the review.

The Letter of Intent is to be sent to:

Scott Janis, PhD
Program Analyst
National Institute of Neurological Disorders and Stroke
Neuroscience Center
Rockville, Maryland 20892
Telephone (301) 496-9135
FAX: (301) 480-1080
email:  janiss@ninds.nih.gov

SCHEDULE SUMMARY

Letter of Intent:                  September 15, 2001
Application Receipt Date:          Nov 15, 2001
Scientific Peer Review:            Approximately March, 2002
Review by NINDS Advisory Council:  May 2002
Earliest Anticipated Award Date:   July 1, 2002

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these awards. These forms are available at most 
institutional offices of sponsored research, from the Grants 
Information Office, Division of Extramural Outreach and Information 
Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 
6095, Bethesda, MD 20892-7910, telephone 301-435-0714, 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/labels.pdf.  Please note 
this is in pdf format.

Submit a signed, original of the application, including the Checklist, 
and three signed photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive Room 1040 MSC-7710
Bethesda, MD  20892-7710 (For express/courier use Bethesda, MD  20817)

At the time of submission, two additional copies of the application 
must also be sent to:

Lillian M. Pubols, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center Suite #3208
6001 Executive Blvd.
Bethesda, MD 20892-9529 (For express/courier use Rockville, MD 20852)
Tel.: 301-496-9223
Fax: 301-402-0182
e-mail: LP28E@NIH.GOV

Applications must be received by Nov 15, 2001.  If an application is 
received after that date, it will be returned to the applicant without 
review.  The Center for Scientific Review (CSR) will not accept any 
application in response to this announcement that is essentially the 
same as one currently pending initial review, unless the applicant 
withdraws the pending application.  The CSR will not accept any 
application that is essentially the same as one already reviewed.  This 
does not preclude the submission of a substantial revision of an 
application already reviewed, but such an application must follow the 
guidance in the PHS Form 398 application instructions for the 
preparation of revised applications, including an introduction 
addressing the previous critique.

--Special Instructions for Preparing Applications for a Clinical Center

Within the Research Plan portions of the applications for the Clinical 
Centers, the following issues should be covered:

o Clinical Centers must be capable of enrolling at least 84 
participants in three and a half years for the pilot studies (n=12) and 
the main clinical trial (n=72).  Applicants should provide 
documentation of the availability of PD patients who are early in the 
course of their disease, including women and racial/ethnic minorities.

o Applicants should document availability and clinical research 
experience of the Clinical Center staff.  Additionally, describe the 
measures that will be implemented to ensure the safety of study 
participants.

o Applicants should describe the clinic environment where the study 
visits will be conducted.

o Applicants should document prior involvement (if any) in single-
center and multi-center clinical trials, including experience in 
recruiting and following PD patients and patients with other 
neurological disorders, and experience in completing data collection 
forms in an accurate and timely manner.

o If the Clinical Center will be a consortium of local sites, 
applicants should describe the history of the consortium and how it 
will operate to ensure uniform patient care and compliance with the 
protocol.  Additionally, describe the advantages of the collaboration 
in terms of cost and recruitment capabilities.

o Clinical Centers must form alliances with PD patient advocates in 
their local areas in order to facilitate recruitment and follow-up of 
study participants.  Applicants should document existing alliances or 
describe alliances they intend to establish.

o Applicants should describe their plans for recruiting study 
participants, including women and racial/ethnic minorities, retaining 
them in the study, and encouraging them to adhere to the protocol.

o Applicants must include an explicit statement of willingness to 
cooperate with the other centers in the conduct of one or more clinical 
trials testing agents approved by the Oversight and Steering 
Committees. 

o Clinical Center applicants are encouraged, but not required, to 
include creative ideas about study design and discussion of the issues 
surrounding neuroprotection trials in PD, as well as to propose and 
justify one or more neuroprotective agents for testing.  

Please see the Review Considerations.

Budget Instructions for Clinical Centers: The maximal budget is $73,500 
direct costs per year for each Clinical Center, to include salary 
support for a research nurse coordinator, physician investigator(s) 
participation, required travel to training workshops and annual 
investigator’s meetings ($1500 per year maximum), and all other 
required activities.  Receipt of the full award amount is contingent 
upon recruitment of 2 participants per month during the 9 month pilot 
phase (n=12) and in the three-year main trial recruitment period (n=72) 
with successful protocol execution (attempted recruitment of all 
eligible patients, timely and complete follow-up and data collection, 
adequate protocol adherence, no participant lost-to-follow-up).  
Clinical Centers that do not participate in individual protocols or 
that do not meet recruitment/execution standards will have the grant 
budget reduced.  For situations in which applicants have existing 
ongoing clinical research in PD, the scientific and budgetary 
implications of potential overlap should be described.  If a center is 
capable of doing excellent research but able to provide fewer or more 
patients than requested, then such applications are welcomed.  The 
requested budgets should be modified in proportion to the proposed 
number of patients.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NINDS. Incomplete or unresponsive 
applications will be returned to the applicant without further 
consideration.  

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the NINDS in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will receive a written critique and undergo a process in 
which only those applications deemed to have the highest scientific 
merit will be discussed, assigned a priority score, and receive a 
second level review by the National Institute of Neurological Disorders 
and Stroke Advisory Council.

Review Criteria

Applications will be judged on the basis of the ability of the 
investigators to fulfill the SPECIAL REQUIREMENTS for each component 
described in this RFA, comply with the cooperative agreement terms and 
conditions of award, and to attain the goals stated above in the 
RESEARCH OBJECTIVE section as demonstrated by the capability and 
expertise documented in the application.  

The specific review criteria are described below.

The final design for the clinical trial will be developed 
collaboratively by the Steering Committee relying largely on the 
expertise of the Coordinating Center and the Statistical Center.  The 
major role of the Clinical Centers is to recruit patients.  The peer 
review group will therefore focus on evidence that the Clinical Center 
applicant can recruit sufficient patients and willingly accept the 
responsibility to meet or exceed all requirements for human subject 
protection.

Recruitment Capability:  Is there evidence of prior experience in the 
recruitment of Parkinson patients to clinical trials?  Are there 
realistic plans for the recruitment of patients, including women and 
minority participants for the proposed clinical trial?  Does the 
application provide credible estimates of recruitment capability 
supported by detailed data derived from the current population of 
Parkinson patients that demonstrate all of the characteristics required 
by the trial selection criteria (clinical diagnosis of PD, recent 
diagnosis soon after first symptoms develop, not taking drugs that 
induce Parkinsonism, absence of other disease likely to prevent 5-year 
follow-up.  Patients may be recently started on dopaminergic 
treatment).  Is there sufficient evidence based on prior experience in 
clinical trials, chart reviews, and from other documents that the 
center will be likely to recruit sufficient patients?  If patient 
availability is limited at the primary institution, are there 
satisfactory agreements with other institutions or clinics in the same 
geographic area?  If the recruitment plans include more than two 
clinical sites at one Clinical Center are adequate measures proposed to 
ensure uniform patient care and compliance with the protocol?  Does the 
Clinical Center have evidence of the percentage of eligible Parkinson 
patients who have agreed to participate in previous trials?  Are the 
advantages of collaboration in terms of cost and recruitment 
capabilities (including the recruitment of minorities and women) 
clearly described?  Is the organizational/administrative plan for such 
arrangements clearly delineated and efficient?

Retention Capabilities: Are there complete plans and/or experience in 
achieving high rates of follow-up of trial participants and promoting 
high levels of adherence to the protocol?

Environment:  Does the environment in which the work will be done 
contribute to the probability of success?  

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

The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will 
also be evaluated.

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

The adequacy of the proposed protection for humans, animals, or the 
environment, to the extent they may be adversely affected by the 
project proposed in the application.

The adequacy of the proposed plan to share data, if appropriate.

AWARD CRITERIA

It is anticipated that the earliest award date will be July 1, 2002.  
Applications recommended by the National Institute of Neurological 
Disorders and Stroke Advisory Council will be considered for award 
based upon (a) scientific and technical merit, (b) program balance, and 
(c) availability of funds.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups 
and their sub-populations must be included in all NIH-supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of the research. This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 
103-43).

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: 
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable, and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age 
of 21) must be included in all human subjects research, conducted or 
supported by the NIH, unless there are scientific and ethical reasons 
not to include them. This policy applies to all initial (Type 1) 
applications submitted for receipt dates after October 1, 1998.

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

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

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

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

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT

The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at:  
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

HEALTHY PEOPLE 2010

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

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.853. Awards are made under authorization of Sections 301 and 405 
of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies and Federal Regulations 42 CFR 
52 and 45 CFR Parts 74 and 92. This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.

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



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