PARKINSON DISEASE NEUROPROTECTION CLINICAL TRIAL: COORDINATING AND STATISTICAL CENTERS Release Date: February 27, 2001 RFA: RFA-NS-01-012 National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: March 30, 2001 Application Receipt Date: May 15, 2001 PURPOSE The Neurodegeneration and Clinical Trial Groups of the National Institute of Neurological Disorders and Stroke (NINDS) request applications for centers to collaborate in the performance of a large, double-blind randomized trial of two or more potential neuroprotective agents in patients early in the course of Parkinson’s disease. Two types of applications are requested: for (1) a Coordinating Center, and (2) a Statistical Center. Applications for multiple Clinical Centers will be sought in a separate solicitation. The trial was called for in the NIH Parkinson Research Agenda (http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm). The neuroprotectants to be tested in the trial have not yet been chosen and will be selected from among those proposed by the applicants who respond to this Request for Applications (RFA) as well as from those suggested by others, including NINDS grantees, pharmaceutical companies, patients, and patient advocates. BACKGROUND Parkinson’s disease (PD) affects nearly a million Americans, a number that will increase over the coming decades. While available medical therapies are usually effective for controlling symptoms for the initial years following diagnosis, higher doses of multiple agents are required over time, with increasing side-effects and incomplete control of symptoms. While these treatments can dramatically improve the lives of patients with Parkinson’s disease initially, they have been based on replacing dopamine replacement since the early 1970 s. They do not address the underlying disease cause or the currently inevitable biological progression of PD. The typical course of PD is one of gradual worsening over a decade or more, corresponding to ongoing neuronal loss affecting cells in the pigmented nuclei of the brain, particularly in the substantia nigra. There is a long preclinical phase preceding diagnosis, during which loss of these dopaminergic neurons progresses until the threshold for clinical symptoms is reached, estimated to be about 70-80% loss by the time of diagnosis. Given this prolonged course of progressive neuronal loss, strategies aimed at reducing the rate of neuronal loss or dysfunction (i.e. clinical neuroprotection or disease-modification) are particularly important in this disorder. Effective clinical neuroprotection would importantly reduce PD-related disability for hundreds of thousands of Americans, prompting the National Institute of Neurological Disorders and Stroke (NINDS) to invite qualified investigators to submit grant applications for components of a clinical trial aimed at identifying pharmacological agents to slow the progression of PD. With many potential neuroprotective interventions available, sequential testing of single agents is not the optimal approach to expeditiously reducing disability from PD. Clinical trial designs in which several agents are compared to a single control group have the advantages of participant acceptance because 1) assignment to control is less likely and 2) because of potential to compare directly the active interventions. Factorial designs in which some participants may receive more than one active intervention offer the potential to assess effects of combinations of neuroprotective agents that may work by different mechanisms, although statistical power to define interactions may be limited. Large, simple clinical trials focus on limited goals and a few key outcomes, facilitating participation of large numbers of investigators; supplementing such streamlined protocols, subsets of participants in large, simple trials at selected sites can be more intensively investigated. Despite the substantial disability due to PD, few interventional studies have evaluated agents that might retard disease progression. A previous investigator-initiated trial supported by NINDS, Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), evaluated selegiline (Deprenyl)and vitamin E as treatments for PD. Vitamin E was found ineffective, and selegiline has not become widely used because of uncertainty about a neuroprotective vs. symptomatic effect due to an initially unsuspected dopa-agonist action. The Parkinson Agenda for the NIH was published in April, 2000 (http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm). The agenda calls for the initiation of randomized controlled clinical trials to test potential neuroprotectants. Expert advice regarding implementation of this initiative was solicited at the meeting Therapeutic Initiatives in Parkinson Disease convened by the NINDS (13-Oct-00, Bethesda), which included representatives of several NIH Institutes and national experts in PD and clinical research in neurodegenerative disorders. RESEARCH OBJECTIVE To demonstrate convincingly in a randomized, double-blind clinical trial the efficacy of one or more pharmacological agents for slowing progression of PD and to determine the toxicity and tolerability of such agents. Design of a clinical neuroprotection trial. Final design of the clinical trial will result from collaboration between and consensus of the Coordinating Center, NINDS scientific staff, the Statistical Center, Principal Investigators from Clinical Centers, and the NINDS Oversight Committee (see Study Organization, below). It is anticipated that key elements of the trial will include the following: 1) Inclusion of PD patients relatively early after diagnosis who have at least two of the four cardinal signs. 2) Design capable of detection of small treatment effects because of the clinical importance of even modest benefits to PD patients. 3) General design as a large, simple trial, including large sample size (about 3000 participants), infrequent regular follow-up, and limited data collection, focusing on functional and disability-related outcomes, including those that can be assessed without direct patient contact using either mail or telephone. 4) Prospective plans to distinguish neuroprotective effects from occult symptomatic benefits. The trial will involve the following phases: 1) Selection of potential neuroprotective agents. 2) Pilot studies to develop dose and safety information, to select pharmaceutical agents useful for the main trial, and to refine outcome measures (approximately one year). 3) Main multi-arm trial (approximately 6 years). 4) If necessary, post-trial administration of one or more apparently efficacious neuroprotective agents to all participants to assess occult symptomatic effects and convincingly establish neuroprotection (six months to one year). The entire trial may last up to eight years. Participants in the trial will be enrolled in the earliest stages of the disease possible, and may or may not require symptomatic therapies (depending on the final approved study design). Based on observations from the initial and second randomization in the DATATOP trial, it is anticipated that there will be measurable evidence of disease progression during follow-up averaging three to four years (extending to five years in some participants), both in those receiving dopaminergic agents and those who are not. Outcome instrument development and/or adaptation of existing instruments for use with a large, simple trial design is a key objective of the pilot phase. Use of disability and functional outcome scales sensitive to changes seen during the early course of PD will be emphasized as the primary outcomes. Effects on non-motor features will be included. At present, available biomarkers have not been adequately validated as correlating with clinically relevant neuroprotection to substitute for clinical outcomes in the large phase III clinical trial. Assessment of biomarkers for screening and in selection of neuroprotective agents will be considered. Since biomarkers as surrogate outcomes require validation by correlation with clinical outcomes in positive clinical trials, the concomitant assessment of biomarkers in the large neuroprotection trial, particularly at selected centers or patient subsets, will also be considered, balancing expense and complexity with the overall goals of the large trial. Several candidate agents for neuroprotection testing will likely emerge from this RFA. Because even a small neuroprotective effect with a minimally toxic agent would be important to detect, a relatively large trial is required. Minimizing the cost for each participant will permit larger numbers of participants and make it possible to evaluate more potential neuroprotective agents. The boundary presented by large sample sizes and the cost of conventional studies needs to be crossed in order to obtain the initial success required to sustain research of further neuroprotective treatments. Detecting small effects requires large sample sizes, but it does not mandate a complex protocol. Rather, intermediate contact by mail or telephone, allowing less frequent clinical contact, may provide the needed data at many time points, and reduce costs. It is anticipated that highly reliable functional outcome or disability scales that are multi-modal can be included to simplify outcome measures and reduce the cost of the trial. Several design issues common to large, simple trials must be considered and addressed. Compliance is a major concern, particularly if one or more of the treatments being tested is generally available either over- the-counter or through prescription. Dropouts and patients lost to follow-up must be minimized. Inexpensive methods to maintain patient loyalty and protocol adherence between infrequent clinic visits will be important for successful execution. Reliable outcome measures assessed by different clinicians and other medical professionals are necessary, since primary care providers may have more ready access to a patient than the neurologist. It may also be helpful to enlist the support of PD patient advocacy groups to help build and maintain patient loyalty. Rapid recruitment and initiation of treatment are essential, facilitated by limited inclusion/exclusion criteria. Limited exclusion criteria will expose a broad spectrum of PD patients to the selected neuroprotective drugs, a likely advantage in the initial clinical trials (when the characteristics that predict a patient’s response to a particular drug are not known, the chances of detecting any effect increase if there are a wide spectrum of PD patients participating in the study). If neuroprotective effects are detected, further studies may then define appropriate selection criteria. Participants will reflect the gender and racial/ethnic composition of the U.S. citizens with PD. Studies that test simultaneously multiple agents can be more efficient than a series of trials testing a single agent, making use of a single control group and allowing comparison of agents and combinations of agents. A major intent of this RFA is to encourage active involvement of the Statistical Center in all phases of the clinical trial development, contributing creative input for statistical design and trial management. New designs and methodologies not previously applied to neurodegenerative disease are sought. Specific design issues relevant to neuroprotection trials in PD require careful consideration, with potential solutions incorporated into trial design: 1. Unequal use of other symptomatic PD treatments during the course of the trial that may modify progression (i.e. the putative neurotoxicity of levodopa). 2. Occult symptomatic effects that may confound assessment of neuroprotection. 3. Selection of optimal outcome measures, particularly functional and disability scales appropriate for early PD patients followed for a mean of 3-4 years. 4. Testing of multiple agents in parallel and/or factorial designs. Innovative approaches to these design issues are required. Sample size requirements for testing individual agents will vary according to the estimated minimum clinically important benefit associated with individual agents, the choice of outcome measures and their anticipated change during the planned period of observation (a mean of four years) of up to 3024 participants. Soliciting putative neuroprotective agents for testing will be from several sources and is likely to identify numerous agents linked to and justified by hypothesized mechanisms of neurodegeneration in PD, but other methods for identifying potential agents will also be considered. These will not be limited to compounds already approved by the US Food and Drug Administration. Pharmaceutical companies may have investigational treatments that are potential neuroprotectants, but that are not being developed for PD for reasons unrelated to their potential efficacy. Agents proposed by the successful applicants, biomedical research companies, pharmaceutical companies, research scientists, and patients/PD advocates will be solicited and considered. Final selection of agents will be made by the NINDS-appointed Oversight Committee in collaboration with the Coordinating Center, the Statistical Center and advice from experts in the field. Pilot data to determine the maximum safe dose for PD patients is not likely to be available for all agents to be tested, and a pilot study may be needed for most agents. Pilot trials should determine dose, safety, assess the presence of a dopaminergic effect, and refine/test outcome measures. These pilot studies may be critical to the eventual success of the subsequent large, definitive trial. Consequently, an initial pilot phase for testing each of the agents will be available as part of the planning phase for the trial. STUDY ORGANIZATION The organizational structure will consist of the following components: 1. The Coordinating Center will develop and manage the protocol, assure compliance with regulations, supervise and encourage recruitment, collect, store, and maintain data from clinical centers including recruitment and dropout data, prepare blinded reports on adverse events, monitor study execution at clinical sites, and supply study medications to each site. The principal investigator of the Coordinating Center will serve as chair of the Steering Committee. The Coordinating Center will be blinded to treatment group during recruitment and follow-up in all trials. 2. The Statistical Center will be involved in study design, in planning and performing analysis, and prepare all summary reports to the Coordinating Center, Oversight Committee and NINDS-appointed Data and Safety Monitoring Board (DSMB). 3. Clinical Centers (initially 42 sites) will recruit and follow participants, emphasizing participant adherence and the highest standards of protocol execution. Representatives of Clinical Centers will selectively participate on the Steering Committee. During the trial, Clinical Centers may be added, deactivated, or placed in a follow-up mode with budget reduction, depending on performance and recruitment requirements and requirements protecting human subjects. These will be solicited through a separate RFA. In addition, there will be three key committees: 1. The Oversight Committee will be organized by the NINDS and include NINDS clinical directors and program directors with expertise in preclinical science of neuroprotection and in clinical trials, together with extramural experts in PD and neurodegeneration and with representatives of PD advocacy groups. The Oversight Committee will give final approval to the agents to be tested, approve the final study protocol and plans for analysis developed by collaboration between the Coordinating Center and Statistical Center, evaluate and approve all protocol changes during the course of the trial. 2. The Data Safety Monitoring Board will monitor study execution and safety issues, propose and consider interim analyses. It will be appointed by the NINDS and include a non-voting NINDS representative who will act independently of the NINDS Scientific Program Director (see below). 3. The Steering Committee will consist of the Coordinating Center principal investigator (who will chair the committee), the Principal Investigator of the Statistical Center, NINDS Scientific Program Director, and selected members drawn from the Clinical Centers. The specific membership and charter of the Steering Committee will be proposed by the Coordinating Center and approved by the Oversight Committee. The Steering Committee will approve the final protocols, supervise overall execution of the trial, generate and approve study policies, consider modifications of the protocol and operations, as well as plan and draft study-related publications. The NINDS will name a Program Director whose function will be to expedite the activities outlined under Terms and Conditions (below), and serve as representative for the NINDS to the trial components. The NINDS Program Director will participate on the scientific committees of the trial, but she/he will not be responsible for fiscal management. STUDY TIMETABLE It is anticipated that one large simple randomized, placebo-controlled clinical trial will be completed during the 8 year period of this initiative. In addition, one or more pilot studies may be done for each of the proposed therapeutic agents to determine safety, dose, and feasibility parameters. Although the tentative timetable below indicates that multiple simultaneous pilot studies succeeded by one large simple clinical trial of multiple agents will be performed, the actual number of protocols implemented may vary depending upon the specific study designs agreed upon. Year I: o Protocol development for pilot studies (3 months). o Patient recruitment and follow-up for several simultaneous pilot studies (6 to 9 months). Up to 12 patients per Clinical Center (n=42) will be recruited (total 504). o Protocol development for clinical trial will be ongoing for entire year and completed with a full manual of operations during the last three months of the first year. The manual of operations will be produced by the Coordinating Center in cooperation with the Statistical Center. Year II: o Patient accrual will begin at 42 centers and continue for 36 months at an average rate of two patients per month per center (total = 3024 participants). Year III: o Patient accrual and follow-up in the manner of a large simple trial. Year IV: o Patient accrual and follow-up in the manner of a large simple trial. Year V: o Patient follow-up in the manner of a large simple trial. Year VI: o Patient follow-up in the manner of a large simple trial. Year VII: o Patient follow-up in the manner of a large simple trial for six months. o Start of the post-trial treatment for six months of placebo patients with selected treatments from the main phase of the trial (if necessary, depending on study design). This study after the completion of the main trial will require additional follow-up of patients in one or more arms of the trial. Year VIII o End of the post-trial treatment for six months of placebo patients with selected drugs from the main phase of the trial. o Closeout, data audit, data analysis, and preparation of papers for publication will occur during this last year. Additional years may be required depending on the start date, the time required to complete the pilot studies, and the rate of recruitment for the main trial. SPECIAL REQUIREMENTS The intent of this RFA is to solicit applications from qualified investigators proposing to serve as the Coordinating Center or the Statistical Center in order to conduct a large, collaborative randomized double-blind trial testing neuroprotective agents in patients with early PD. The final study design will be developed through collaboration between the Oversight Committee, Coordinating Center, NINDS Scientific Program Director, and Statistical Center. -- Special Requirements -- The Coordinating Center The Coordinating Center will develop (with the Statistical Center and NINDS Scientific Program Director), implement and manage the study protocols and manuals of operation for the pilot and full-scale multicenter trials, provide overall leadership for the Clinical Centers during recruitment and follow-up, collect, store, and maintain data from the Clinical Centers, and assure quality control and blinded monitoring of data. Ongoing monitoring of performance of the Clinical Centers will be done. The Coordinating Center will work cooperatively with Clinical Centers, a separate Statistical Center, and the NINDS staff. Design and generation of data forms, data entry systems and intra-component communications systems will be undertaken by the Coordinating Center in collaboration with the statistical center. The staff of the Coordinating Center will be required to travel to meetings during the planning phases for development of the study designs, protocols, study manuals of operations, and data forms. It will manage the logistics of all committee activities during the pilot and main trials and will produce minutes of these meetings. In addition to proposing and organizing the meetings required for collaboration between the components, the Coordinating Center will be expected to maintain close communication with the NINDS Scientific Program Director, each Clinical Center, cooperating patient advocacy groups, and the Statistical Center. The Coordinating Center will be responsible for developing procedures to assure that all participants provide appropriate consent prior to participation in any aspect of the study, to assure compliance with federal regulations at each study site, to adhere to NINDS, FDA and (if appropriate) pharmaceutical company procedures for adverse event reporting. The Coordinating Center will recommend two or more potential neuroprotectant agents for testing, accompanied by thorough justification of each agent (ultimate choice of the specific agents and number of treatment arms will be made by the Oversight Committee in collaboration with the Coordinating and Statistical Centers after the grants are awarded). Applicants are encouraged to contact pharmaceutical manufacturers of agents proposed for the trial to determine their interest in participating in protocol development and to provide both drug and placebo for testing in the trial. An estimate of the risks expected from the prolonged use of any proposed agents should be provided, if known. In addition, the investigators should discuss acceptable risks for neuroprotective treatments for Parkinson disease. Applicants are requested to determine the level of interest of these manufacturers in participating in the trials to be conducted, including providing drug to the investigators. The results of these discussions should be clearly described in the grant application. If a pharmaceutical company wishes information to be collected that is not necessary for the scientific conduct of the trial, the cost of this additional information is to be borne by the company and the data is to be gathered in such a way that does not threaten the blinding or execution of the trial. The Coordinating Center will propose criteria for selecting two or more neuroprotective agents from those likely to be elicited in response to this RFA (i.e. in addition to those agents proposed in the Coordinating Center application). These criteria should consider anticipated magnitude of benefit, toxicity, strength of preclinical evidence (including biomarkers) suggesting benefit. Applications for the Coordinating Center should address key design issues pertinent to demonstrating clinical proof of neuroprotection (i.e. what constitutes convincing clinical evidence of neuroprotection? This is not meant to imply that agents that have symptomatic effect could not also be neuroprotectants.) Inclusion/exclusion criteria and recruitment strategies should be included in the application that are consistent with the overall research objective of this RFA. Outcome measures relevant to neuroprotection trials should be proposed and their rate of change/event rate estimated. A general plan and budget for drug distribution to the Clinical Centers should also be included. Plans for assuring protocol adherence and complete follow-up of all study participants, including early identification of problem Clinical Centers, should be part of the application. Plans for central adjudication of eligibility and outcomes (including adverse events) and an appropriate budget for adjudicators (consulting costs, telecommunication, travel) is the responsibility of the Clinical Coordinating Center. Training for investigators from the Clinical Centers will be provided by the Coordinating Center. -- Special Requirements -- The Statistical Center The Statistical Center will have an important role in all aspects of the project, offering creative approaches to study design, execution, and ongoing monitoring and analysis. This includes proposals for distinguishing neuroprotective vs. symptomatic effects and options for innovative study designs that will permit the maximum number of agents to be tested, considering potential interactions, balancing magnitude of treatment effects with a maximal total sample size of about 3024 participants. Proposals for specific trial design await selection of the specific agents to be tested, but demonstration of capability and innovative approaches to design of trials with multiple agents and long follow-up periods is crucial to the application. It is the intent of this RFA that the Statistical Center be operationally independent of the Coordinating Center, in order to stimulate creative interactions, to facilitate maintaining the blind, and to offer independent assessment of the ongoing trial performance and data quality. The Statistical Center will work with the Coordinating Center to develop the study protocols for the pilot and main trials (for approval by the Oversight Committee) and procedures for monitoring quality control and participant safety. It will ensure consistency of the final data forms with the protocols and assure that the final forms contain all data necessary to perform appropriate analysis of the trial and pilot studies. It will perform tests of the consistency of the data. It will prepare periodic reports for the DSMB (performing the required interim analyses). It will prepare interim reports for the Coordinating Center on performance of the Clinical Centers, including recruitment, patient safety, and data quality. It will perform all analyses for publication of trial data and prepare archival records of the trial. The Statistical Center will arrange central adjudication of outcomes relating to efficacy and safety (as required by the final study protocol). The Statistical Center will develop procedures for and monitoring of blinding of administration of the study interventions. The staff of the Statistical Center will be required to travel to meetings during the planning phases and to participate on the Steering Committee and other subcommittees. As a general rule, each individual Principal Investigator will be responsible for allowing important breakthroughs resulting from this work to become available to the clinical community through the literature, through preparation and submission of manuscripts and abstracts to appropriate journals in a timely fashion. TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the notice of grant award, which is provided to the Principal Investigator and the Institutional Official. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and the NIH Grants Policy Statement. 1) Collaborative Responsibilities. The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NINDS scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NINDS purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NINDS Program Director and NINDS-appointed Oversight Committee. The study will be lead by a Steering Committee. Members of this Committee will include the Principal Investigators of the Coordinating Center and Statistical Center, the NINDS Scientific Program Director. After Clinical Centers are activated, the Principal Investigators of two Clinical Centers will be chosen by the other three members and approved by the Oversight Committee. The chair of the Steering Committee will be the Principal Investigator of the Coordinating Center. The Steering Committee may appoint subcommittees to perform specific tasks; one will be a Publication Subcommittee to establish publication policies and approve publications prior to submission. 2) Awardees Rights and Responsibilities. Coordinating Center The awardees for the Coordinating Center will: a) In conjunction with the Clinical Centers, the Statistical Center, and NINDS, lead the development of the trial designs and manuals of operation. b) Collect, store, and evaluate the quality of the data transmitted by the Clinical Centers. c) Monitor performance of Clinical Centers in implementing the protocols d) Transmit the study database to the Statistical Center on a regular basis. e) Manage meetings of the Steering Committee. f) Attend blinded portions of the PSMB as requested g) Ensure that recruitment of patients proceeds on schedule h) Provide training for the clinical coordinators and investigators at the clinical centers. i) Recommend neuroprotectants for inclusion in the project. j) Provide a system for drug distribution. k) Make all required safety reports and provide an in-house safety monitor to review safety data and assist the Statistical Center in preparation of reports to the DSMB. l) The Coordinating Center will coordinate, through a Publications Committee, the preparation and publication of scientific results of the pilot and main studies. In order to protect the integrity of the trial, the Coordinating Center will assure that no public or scientific presentations of the results of a pilot trial or the main trial are made until the primary report for the trial has been accepted for publication (there will be no exception to this rule unless recommended by the DSMB to protect participants or for public safety). m) Carry out the other elements of the research project as described in this RFA. The awardees for the Statistical Center will: a) Participate extensively in the design of each pilot study and the large simple clinical trial. This includes development and characterization of outcome measures. b) Develop efficient and innovative statistical approaches to the pilot studies and large simple trial performed by this collaboration. Encourage a creative approach on the part of the Coordinating Center and Clinical Centers. c) Act to reduce bias and protect any blinding during the entire project. d) Provide interim reports on the progress of the Clinical Centers, including reports on recruitment and data quality e) Provide analyses and reports for the Steering Committee, Data and Safety Monitoring Board, and the National Institute of Neurological Disorders and Stroke. f) Conduct analyses of the data from the pilot studies and the large trial for publication in peer-reviewed scientific journals. g) Anticipate and participate in the solution of problems with recruitment at participating centers. h) Provide a copy of the final study database for archival. i) Carry out the research project as described in this RFA. Awardees will retain custody of and primary rights to their data developed under the award, subject to government policies regarding rights of access. In accordance with the policies and procedures established by the Steering Committee, all Clinical Center awardees will be required to provide study data to the Coordinating Center. The Coordinating Center will, in turn, be required to transmit all data to the Statistical Center. The data will be stored at the end of the trial in a format suitable for archival in a United States national repository at a time when the investigators no longer have a use for the data. A plan for eventual placement in a national archive will be developed by the grantees and approved by the NINDS. 3) NINDS Responsibilities. The NINDS will name the Scientific Program Director for the study. The Program Director’s function will be to assist the Steering Committee, the Publication Committee , and other subcommittees in carrying out the trials, including quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and coordination of efforts of all the project centers. The NINDS Program Director will have voting membership on the Steering Committee, and as appropriate, other subcommittees of the Steering Committee including the publications committee. To the extent that the NINDS Scientific Program Director contributes to the scientific content of the trial, authorship may be shared in publications with other investigators in accordance with the same policies of the Publication Committee that apply to other investigators. A second NINDS Program Scientist will administer the cooperative agreements and will be responsible for the fiscal management of the program at the NIH. Other NINDS scientists may, as appropriate, attend meetings and serve on study committees and work with awardees on issues coming before the Steering Committee or its subcommittees. However, in all cases, the NINDS will have only a single vote on study committees, either of the whole or on subcommittees. The NINDS will appoint and support the travel and other expenses of a Data Safety and Monitoring Board, either directly or through a supplement to the Coordinating Center grant. The NINDS reserves the right to terminate or curtail the study (or an individual award) in the event of (a) a major breach in the protocol or substantial changes in the agreed-upon protocol with which the Institute does not agree or (b) human subject ethical issues that may dictate a premature termination or (c) failure to pursue the objectives stated in this Request for Applications, or (d) substantial shortfall in recruitment and/or retention of subjects or (e) a recommendation to the NINDS by the DSMB to stop a pilot study or the large trial. 4) Governance An Oversight Committee will appointed by the NINDS. It will not include the NINDS Scientific Program Director who is a member of the Steering Committee or members from the same institution as any Center in the project. It will include the NINDS Associate Clinical Directors, an NINDS program scientist with expertise in pre-clinical research, outside experts in clinical research and Parkinson Disease, patient advocates and an expert in ethics. Protocols, protocol modifications, and choice of interventional agents will be reviewed and approved by the Oversight Committee. The Steering Committee will comprise the Principal Investigators of the Coordinating Center and the Statistical Center, the NINDS Scientific Program Director, and two Principal Investigators from the Clinical Centers selected by the other members of the Steering Committee and approved by the Oversight Committee. Initial representation of the Clinical Centers on the Steering Committee will be based on the availability of expertise in relevant approaches to study design and selection of neuroprotective agents. After patient recruitment begins, membership from the Clinical Centers will rotate and be based on recruitment and execution. The Steering Committee will have primary responsibility for developing common clinical protocols and obtaining approval of the protocols by the NINDS Oversight Committee. They will also facilitate the conduct and monitoring of the trials, and reporting the study results. Each member of the Steering Committee will have one vote, and all major scientific decisions will be determined by majority vote of the Steering Committee subject to approval by the NINDS Oversight Committee. The Chair of the Steering Committee will be the Principal Investigator of the Coordinating Center. All protocol changes must be approved by the Oversight Committee. Steering Committee meetings will most often take place via teleconference call, at least every six months. Subcommittees appointed by the Steering Committee and comprised of Principal Investigators and appropriate staff from the Clinical Centers, the Coordinating Center, and the Statistical Center will be involved in the design of the protocols and the manual of operations, and in ongoing functions of the trials, such as review of ancillary studies and preparation of publications. Not all Clinical Centers will necessarily be represented on all subcommittees. The NINDS program director may choose to participate in any of the meetings of these subcommittees. The Director, NINDS, will appoint an independent Data and Safety Monitoring Board, to review periodically the progress of the trials. It will be comprised of experts in relevant medical, statistical, operational, and bioethics fields who are not otherwise involved in the study. The Data and Safety Monitoring Board will oversee participant safety, approve procedures for blinding, evaluate results, monitor data quality, and provide operational and policy advice to the NINDS in accordance with the policies and procedures of the NIH and the NINDS. The Principal Investigator of the Coordinating Center, the Principal Investigator of the Statistical Center, the NINDS Program Director may be invited to attend Data and Safety Monitoring Board meetings, but will not attend unblinded sessions of those meetings. 5) Arbitration. Any disagreement that may arise in scientific- programmatic matters between award recipients and NINDS may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NINDS not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NINDS, and a third member selected by the preceding two members. These special arbitration procedures in no way affect the awardee’s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulations at 45 CFR Part 16. The conditions of award will apply and have precedence in all disagreements unless mutually agreed by both NINDS and the awardee. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreements are discussed later in this document under the section "Terms and Conditions of Award." The modular grant mechanism will not apply for either of the two different types of applications. The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is September 30, 2001. This is a one time solicitation for applications. In order to complete the eight-year project to be proposed in response to this RFA, competitive renewal applications will be solicited for peer review from the successful applicants four years after the project starts in order to facilitate continuous funding beyond five years. The number of awards to be made and level of support to be provided depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the National Institute of Neurological Disorders and Stroke, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. FUNDS AVAILABLE It is expected that approximately $1,470,000 total cost (direct plus Facilities and Administrative costs) will be available each year over a five year period for the Coordinating and Statistical Centers. It is anticipated that one award for the Coordinating Center will be made for approximately $800,000 direct cost per year, and one award for $250,000 direct cost per year for a Statistical Center. Later, in response to a separate RFA it is anticipated that 42 awards for Clinical Centers will be made. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, clinics, laboratories, units of State and Local governments, and eligible agencies of the Federal Government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. It is the intent of the RFA that the Statistical Center and the Coordinating Center be functionally independent in order to preserve blinding and to solicit independent reports on the performance of the Coordinating Center from the Statistical Center, and vise-versa, for the Oversight Committee. INQUIRIES Written, including electronic mail, and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific or programmatic issues to: Scott Janis, Ph.D. Clinical Trial Group National Institute of Neurological Disorders and Stroke Neuroscience Center 6001 Executive Blvd. Rockville, MD 20892 Telephone: (301) 496-9135 FAX (301) 480-1080 Electronic mail: janiss@ninds.nih.gov Direct inquiries regarding fiscal matters to: Gladys Bohler Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd. Rockville, MD 20892 Telephone: (301) 496-9231 FAX (301) 402-0219 Electronic mail: bohlerg@ninds.nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by March 30, 2001, a letter of intent that includes a descriptive title of the proposed research; name, address, and telephone number of the Principal Investigator; identities of other key personnel and participating institutions; and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information allows NINDS staff to estimate the potential review workload and to plan the review. The Letter of Intent is to be sent to: Scott Janis, PhD Program Analyst National Institute of Neurological Disorders and Stroke Neuroscience Center Rockville, Maryland 20892 Telephone (301) 496-9135 FAX: (301) 480-1080 email: janiss@ninds.nih.gov SCHEDULE SUMMARY Letter of Intent: March 30, 2001 Application Receipt Date: May 15, 2001 Scientific Peer Review: Approximately August 1, 2001 Review by NINDS Advisory Council: September 13-14, 2001 Anticipated Award Date: September 30, 2001 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these awards. These forms are available at most institutional offices of sponsored research; from the Grants Information Office, Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form and the YES box must be marked. The RFA number must be typed on the label as well. The sample RFA label is available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is in pdf format. Submit a signed, original of the application, including the Checklist, and three signed photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive Room 1040 MSC-7710 Bethesda, MD 20892-7710 (For express/courier use Bethesda, MD 20817) At the time of submission, two additional copies of the application must also be sent to: Lillian M. Pubols, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke Neuroscience Center Suite #3208 6001 Executive Blvd. Bethesda, MD 20892-9529 (For express/courier use Rockville, MD 20852) Tel.: 301-496-9223 Fax: 301-402-0182 e-mail: LP28E@NIH.GOV Applications must be received by May 15, 2001. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. --Special Instructions for Preparing Applications -- Coordinating Center The Research Plan of applications for the Coordinating Center may exceed the usual 25 page limit, but should not exceed 35 pages. Data collection forms, sample consent forms, and other key elements of a manual of operations may be included in an appendix for reference. Within the Research Plan of the applications for the Coordinating Center, the following issues should be addressed: o Applicants should present their recommendation and justification for selection of two or more agents to slow or stop the progression of Parkinson Disease. In addition they should discuss the availability of the agents recommended and the necessity for doing pilot studies. Applicants should propose primary and secondary outcomes for randomized clinical trials of drug therapy to slow or stop the progression of Parkinson disease. It is anticipated that the pilot studies and large simple clinical trial will be conducted among a broad group of Parkinson patients recently diagnosed or recently started on and responsive to dopaminergic therapy. Experience in data management, including development of data collection instruments and database management and integrity should be described. Applicants should propose study designs for any necessary pilot studies and a subsequent large simple trial to be conducted over the course of this project. Solutions should be suggested for potential problems related to the design and conduct of such trials. The applicant’s study design should propose methodology that limits the amount of information collected on each patient, but maximizes accuracy and reliability of the information that is collected. This methodology should include efficient mechanisms for ensuring patient compliance and long term participation in the study. In addition, selection criteria should be specified which include a broad spectrum of Parkinson disease and that will not impede rapid recruitment of a large number of patients. Applicants should provide a justification for the subject selection criteria, and the projected time necessary for recruitment. Applicants must propose primary and secondary outcomes. The primary outcome must be a reliable test of patient function or disability. A proposal for evaluating different candidate treatments in order to select a specific drug for the proposed trial should be provided. o In cases where applicants have an existing clinical research program in PD ongoing, the scientific and economic implications of any overlap should be outlined in the application. o The Coordinating Center application should explain how the proposed center will relate with other components in this collaborative project. As the study protocols will require extensive collaboration between the Statistical Center, and Steering Committee, applicants should demonstrate the ability to work effectively with interdependent groups to provide input on all aspects of study design and execution. o Since this research proposes a phase III clinical trial, careful attention must be paid to the policies described below in the section entitled INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS. o Budget Instructions for Coordinating Center: The five-year budget in the application for the Coordinating Center should provide for expertise in Parkinson disease and leadership of a major multicenter clinical trial. For ease of review and administration, it is requested that the Coordinating Center budget contain a separate budget page for data management. Salary: Enter the dollar amounts for each position for which funds are requested for all staff in each Center. Computer and Data Management support should be included in the Coordinating Center budget. It should also include a clinical coordinator responsible for training of Clinical Center coordinators and facilitating the flow of data; and the administrative support necessary for the communication required for leading a large collaborative clinical trial; and staffing for ensuring patient safety, medical review of possible adverse events, and reviewing compliance with selection criteria. Salary limitation on grants and cooperative agreements and contracts can be accessed at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-013.html. Consultant costs: Provide the names and organizational affiliations of all consultants whether or not funds are requested. Include the anticipated duration of consultation and the expected rate of compensation, travel, per diem, and other related costs. Equipment/Supplies/Other Expense: List each item of equipment separately. Itemize supply categories for amounts above $1000. Itemize Other Expenses by category and unit cost. Allowance should be made for drug distribution, but not the cost of purchasing drug or placebo; drug distribution, but not the cost of purchasing drug or placebo. Travel: Include travel to organizational meetings, Steering Committee meetings and other meetings, and site visits for quality control. For planning, assume that all study meetings that involve more than one center would occur in Bethesda, Maryland. Monthly travel to meetings in Bethesda, Maryland, for the first 3 months of the trial, and quarterly thereafter should be planned (alternate meeting schedules can be proposed). Consortium/Contractual Costs: If there is a need for consortium activity, submit a separate detailed initial budget and projected budget for the proposed project period for each participating consortium/contractual organization. --Special Instructions for Preparing Applications -- Statistical Center Within the Research Plan portions of the applications for the Statistical Center, the following issues should be covered: o A proposal for a design for a clinical trial of 2 to 6 different drugs to prevent or stop the progression of Parkinson’s disease. Possible alternative designs should also be discussed. The number of different drugs to be tested will be limited by the total sample size of 3024. The application should propose how the Statistical Center could participate in the drug selection process. The specific trial design awaits selection of the agents to be tested and of outcome measures and their change during observation, but demonstration of capability and innovative approaches to the design and execution of neuroprotection trials in PD is crucial to the application. o The Statistical Center application should explain how the proposed center will relate with other components in this collaborative project. As the study protocols will require extensive collaboration between the Statistical Center and the Coordinating Center and Steering Committee, applicants should demonstrate the ability to work effectively with clinicians to provide input on all aspects of study design and execution. o Specific plans should be presented for monitoring of data quality. o A major emphasis should be placed on the demonstration of the capability to develop new trial designs to address the special challenges presented by clinical trials for neuroprotectants for Parkinson’s disease that are described above. o The application should demonstrate that the statistical center has appropriate expertise in the design and analysis of phase I and phase II clinical trials. o Plans for generating the randomization codes and collaboration with the drug distribution center. o Since this research proposes a phase III clinical trial, careful attention must be paid to the policies described below in the section entitled INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS. o Budget Instructions for Coordinating Center: The five-year budget in the application for the statistical center will focus on support for statistical expertise and data analysis for the main trial and any pilot studies. The costs of basic data collection and quality control should not be included in the Statistical Center budget since these activities will occur in the Coordinating Center. However, resources to check for completeness and consistency of key data elements should be included in the Statistical Center budget. Salary: Enter the dollar amounts for each position for which funds are requested for all staff in each Center. Salary limitation on grants and cooperative agreements and contracts can be accessed at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-013.html. Consultant costs: Provide the names and organizational affiliations of all consultants whether or not funds are requested. Include the anticipated duration of consultation and the expected rate of compensation, travel, per diem, and other related costs. Equipment/Supplies/Other Expense: List each item of equipment separately. Itemize supply categories for amounts above $1000. Itemize Other Expenses by category and unit cost. The costs of preparing multiple publications for peer review should be planned for in the Statistical Center budget, including the reporting of results from any pilot phase I/II studies. Travel: Monthly travel to meetings in Bethesda, Maryland, for the first 3 months of the trial, and quarterly thereafter should be planned. Consortium/Contractual Costs: If there is a need for consortium activity , submit a separate detailed initial budget and projected budget for the proposed project period for each participating consortium/contractual organization. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NINDS. Incomplete or unresponsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NINDS in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Institute of Neurological Disorders and Stroke Advisory Council. Review Criteria Applications will be judged on the basis of the ability of the investigators to fulfill the SPECIAL REQUIREMENTS: DUTIES AND RESPONSIBILITES for each component described in this RFA, comply with the cooperative agreement terms and conditions of award, and to attain the goals stated above in the RESEARCH OBJECTIVE section as demonstrated by the capability and expertise demonstrated in the application. The specific review criteria for each component are described below. -- Review Criteria for Coordinating Center The structure of the collaborative group described in this RFA is intended to promote the development of new clinical trial methodology by the interaction between the Statistical Center and the Coordinating Center. Therefore, the review criteria for the Coordinating Center emphasize knowledge of Parkinson disease, clinical scales, clinical protocol design, data management, safety monitoring. Expertise in statistical design and analysis is expected to reside in the independent Statistical Center. Review of applications for the Coordinating Center will be based on the following criteria: - Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? - Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? - Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Demonstrable knowledge of the potential problems associated with the conduct of clinical trials of drug therapy to treat neurodegenerative disease and approaches to their solution will be evaluated. Data Management: Adequacy of the proposed plans and experience relating to data collection, management, editing, processing, quality control, and transmission to the Statistical Center for further checking of consistency and accuracy will be evaluated. - Investigators: Are the investigators appropriately trained and well- suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers? Do the professional, technical, and administrative staff have documented competence and relevant experience specifically pertinent to the operation of a Coordinating Center for a large simple randomized clinical trial of drug therapy to prevent progression of Parkinson Disease? Do they have prior experience collecting data from multiple clinical sites, monitoring the data quality and blinded monitoring of patient safety? Do the proposed Coordinating Center personnel have experience in protecting trial blinding and utilizing procedures to insure the safety and confidentiality of all records? Experience in working with drug packaging and distribution centers: Because the trial will involve multiple treatments, it is anticipated that a central distribution center may be required to furnish both drug and placebo in a timely fashion to the Clinical Centers. The applicants' experience in establishing and working cooperatively with a Drug Distribution Center in cooperative studies will be evaluated. - Resources and Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Reviewers will evaluate the adequacy of the proposed facility, technical hardware, and space and the appropriateness of the organizational and administrative structure of the proposed Clinical Coordinating Center. - Collaboration: Do the investigators demonstrate willingness to work cooperatively with the investigators in other centers participating in the project. Adequacy of the approach to developing a cooperative relationship among the participating Statistical Center and the Clinical Centers and exercising appropriate leadership in matters of study design, data acquisition, data management, data quality, and data analysis. Evidence of experience in and willingness to participate appropriately in a collaborative study as described in this RFA. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. -- Review Criteria for Statistical Center The structure of the collaborative group described in this RFA is intended to promote the development of new clinical trial methodology by the interaction between the Statistical Center and the Coordinating Center. Therefore, the review criteria for the Statistical Center emphasize innovative statistical approaches to the evaluation of treatments of neurodegenerative diseases such as PD. Expertise in PD and other neurodegenerative diseases expected to reside in the Coordinating Center. Review of applications for the Statistical Center will be based on the following specific criteria: - Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? -Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? - Investigators: Are the investigators appropriately trained and well- suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers? Competence: Has the application documented specific competence and relevant experience of professional, technical, and administrative staff pertinent to the design and analysis of a large simple randomized clinical trial of multiple drug therapies to prevent progression of Parkinson Disease and any necessary phase I or phase II pilot studies? Do the proposed investigators demonstrate the capability to design phase I and phase II studies that are innovative and practical? Is it likely that the proposed Statistical Center will be able to lead the application of cutting-edge statistical research to the proposed pilot studies and the main large simple trial? Collaboration: Do the investigators demonstrate willingness to work cooperatively with the investigators in other centers participating in the studies? Have the investigators demonstrated the capability to communicate effectively with clinicians in the collaborative development of protocols? While collaborating with clinical researchers will the Statistical Center investigators demonstrate flexibility and creative adaptability to specific clinical questions rather than procrustean application of conventional methods? - Resources and Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Reviewers will evaluate the adequacy of the proposed facility, technical hardware, and space and the appropriateness of the organizational and administrative structure of the proposed Statistical Center. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. In particular, reviewers will evaluate whether confidentiality will be protected adequately by the proposed Statistical Center. AWARD CRITERIA It is anticipated that awards will be made on September 30, 2001. Applications recommended by the National Institute of Neurological Disorders and Stroke Advisory Council will be considered for award based upon (a) scientific and technical merit; (b) program balance, and (c) availability of funds. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Parkinson Disease Neuroprotection Clinical Trial: Coordinating and Statistical Centers , is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.853. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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