PARKINSON DISEASE NEUROPROTECTION CLINICAL TRIAL: CLINICAL CENTERS RELEASE DATE: September 2, 2004 RFA Number: RFA-NS-05-004 EXPIRATION DATE: January 25, 2005 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.853 LETTER OF INTENT RECEIPT DATE: December 23, 2004 APPLICATION RECEIPT DATE: January 24, 2005 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The Neurodegeneration and Clinical Trial Groups of the National Institute of Neurological Disorders and Stroke (NINDS) request applications for additional clinical centers to collaborate in clinical trials to test potential neuroprotective agents in Parkinson’s disease (PD). These studies, the neuroprotection exploratory trials in PD (NET- PD) include pilot clinical trials and plans for a large, simple phase III clinical trial. Previous solicitations were issued for the clinical and statistical coordinating centers (http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-01-012.html) and clinical centers (http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-02-010.html. Pilot clinical trials are ongoing with over forty participating sites. The agents under study currently include creatine, minocycline, Coenzyme Q10, and a neuroimmunophilin ligand. These pilot studies are expected to complete follow-up in the 3rd quarter of 2005. Depending upon the results of these studies a phase III trial with one of these agents may be conducted or additional pilot studies of different agents may be performed. Sites are sought to join NET-PD to participate in these future studies. RESEARCH OBJECTIVES The ultimate objective is to demonstrate efficacy in a randomized, double-blind clinical trial of one or more pharmacological agents for slowing the progression of PD and to determine the safety and tolerability of these agents. BACKGROUND Parkinson’s disease (PD) affects nearly a million Americans, a number that will increase over the coming decades with an annual incidence of up to 50,000. While available medical therapies are usually effective for controlling symptoms for the early years following diagnosis, higher doses of multiple agents are required over time, with increasing side-effects and incomplete control of symptoms. While these treatments can dramatically improve the lives of patients with Parkinson’s disease initially, they have been based on dopamine replacement. They do not address the underlying disease cause or the currently inevitable biological progression of PD. The typical course of PD is one of gradual worsening over a decade or more, corresponding to ongoing neuronal loss affecting cells in the pigmented nuclei of the brain, particularly in the substantia nigra. There is a preclinical phase of uncertain duration preceding diagnosis, during which loss of these dopaminergic neurons progresses until the threshold for clinical symptoms is reached, estimated to be about 60-70%% loss by the time of diagnosis. Given this prolonged course of progressive neuronal loss, strategies aimed at reducing the rates of neuronal loss or dysfunction (i.e. clinical neuroprotection or disease-modification) are particularly important in this disorder. Despite the substantial disability due to PD, few interventional studies have evaluated agents that might slow disease progression. Effective clinical neuroprotection would reduce PD-related disability for hundreds of thousands of Americans, prompting the National Institute of Neurological Disorders and Stroke (NINDS) to invite qualified investigators to submit grant applications for components of a clinical trial aimed at identifying agents to slow the progression of PD. Currently there are two ongoing pilot studies: one parallel study of creatine (10mg/day) and minocycline (200mg/ day), and a second parallel study of Coenzyme Q10 (2400mg/day) and a neuroimmunophilin ligand, GPI 1485 (4000mg/day). These pilot clinical trials will determine if these agents warrant further study in a phase III trial. This phase III trial would be conducted in the manner of a large, simple trial, with a focus on clinically meaningful endpoints and relatively infrequent follow-up visits. The exact study design depends upon the agents selected and outcome information from the pilot studies. In the event that all pilot trials are negative, additional agents may be tested in further pilot trials. The trials are being conducted at over 40 centers in the United States with the Clinical Coordinating Center at the University of Rochester and the Statistical Coordinating Center at the Medical University of South Carolina. Neuroprotection clinical trials were initially called for in the Parkinson Agenda for the NIH which was published in April, 2000 (http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm. The agenda calls for the initiation of randomized controlled clinical trials to test potential neuroprotectants. Expert advice regarding implementation of this initiative was solicited at the meeting Therapeutic Initiatives in Parkinson Disease convened by the NINDS (13-Oct-00, Bethesda), which included representatives of several NIH Institutes and national experts in PD and clinical research in neurodegenerative disorders. Design of a clinical neuroprotection trial. Final design of future clinical trials will result from collaboration between and consensus of the NET-PD steering committee and the NINDS Oversight Committee (see Study Organization, below). Key elements of the phase III trial will include the following: 1) Inclusion of PD patients early after clinical diagnosis with two or more of the four cardinal signs, not taking drugs that induce Parkinsonism, absence of other disease likely to prevent long term follow-up. 2) Design capable of detection of small but clinically meaningful treatment effects. 3) General design of the phase III study as a large, simple trial, including large sample size (up to 3000 participants), infrequent, regular follow-up, and limited data collection, focusing on functional and disability-related outcomes, including those that can be assessed without direct patient contact using either mail or telephone. 4) Prospective plans to distinguish neuroprotective effects from occult symptomatic benefits. The trial will involve the following phases: 1) Ongoing pilot studies to develop dose and safety information, to select pharmaceutical agents that merit phase III evaluation, and to refine outcome measures (years I-III of the program). These studies will be complete when new sites are added to NET-PD. 2) Selection of additional agents for pilot studies as needed. 3) Main multi-arm trial (approximately 6 years, or more). 4) If necessary, post-trial administration of one or more apparently efficacious neuroprotective agents to all participants to assess occult symptomatic effects and convincingly establish neuroprotection (six months to one year). The entire initiative may last up to nine years, or more. Participants in the trial will be enrolled in the early stages of the disease, and may or may not require symptomatic therapies (depending on the final, approved study design). Based on observations from the initial and second randomization in the DATATOP trial, it is anticipated that there will be measurable evidence of disease progression during follow-up of 3 or more years, both in those receiving dopaminergic agents and those who are not. Outcome instrument development and/or adaptation of existing instruments for use with a large, simple trial design is a key objective of the pilot phase. Use of disability and functional outcome scales sensitive to changes seen during the course of PD will be emphasized as the primary outcomes. Effects on non-motor features will be included. Available biomarkers have not been appropriately validated to substitute for clinical outcomes in the large phase III trial. Assessment of biomarkers for screening and in selection of neuroprotective agents will be considered. Since biomarkers as surrogate outcomes require validation by correlation with clinical outcomes in positive clinical trials, the concomitant assessment of biomarkers in the large neuroprotection trial, particularly at selected centers or patient subsets, will also be considered, balancing expense and complexity with the overall goals of the large trial. Several candidate agents for neuroprotection testing have emerged from the previous RFAs for this trial. Because even a small neuroprotective effect with a minimally toxic agent would be important to detect, a relatively large trial is required. Minimizing the cost for each participant will permit larger numbers of participants and make it possible to evaluate more potential neuroprotective agents. The boundary presented by large sample sizes and the cost of conventional studies needs to be crossed in order to obtain the initial success required to sustain research of further neuroprotective treatments. Detecting small effects requires large sample sizes, but it does not mandate a complex protocol. Rather, intermediate contact by mail or telephone, allowing less frequent clinical contact, may provide the needed data at many time points, and reduce costs. It is anticipated that highly reliable functional outcome or disability scales that are multi-modal can be included to simplify outcome measures and reduce the cost of the trial. Several design issues common to large, simple trials must be considered and addressed. Compliance is a major concern, particularly if one or more of the treatments being tested is generally available either over- the-counter or through prescription. Dropouts and patients lost to follow-up must be minimized. Inexpensive methods to maintain patient loyalty and protocol adherence between infrequent clinic visits will be important for successful execution. Reliable outcome measures assessed by different clinicians and other medical professionals are necessary, since primary care providers may have more ready access to a patient than the neurologist. It will also be helpful to enlist the support of PD patient advocacy groups to help build and maintain patient loyalty. Rapid recruitment and initiation of treatment are essential, facilitated by limited inclusion/exclusion criteria. Limited exclusion criteria will expose a broad spectrum of PD patients to the selected neuroprotective drugs, a likely advantage in the initial clinical trials. (When the characteristics that predict a patient’s response to a particular drug are not known, the chances of detecting any effect increase if there is a wide spectrum of patients participating in the study.) If neuroprotective effects are detected, further studies may then define appropriate selection criteria. Participants will reflect the gender and racial/ethnic composition of U.S. citizens with PD. Pilot data to determine the maximum safe dose for PD patients is not likely to be available for all agents to be tested, and ongoing (and potentially future pilot studies) may be needed. Pilot trials will determine dose, safety, assess the presence of a dopaminergic effect, and refine outcome measures. These pilot studies will be critical to the eventual success of any subsequent large, definitive, phase III trial. STUDY ORGANIZATION The organizational structure currently in place for these studies consists of the following components: 1. The Coordinating Center will develop and manage the protocol (in conjunction with the steering committee and Oversight committee), assure compliance with regulations, supervise and encourage recruitment, collect, store, and maintain data from clinical centers including recruitment and dropout data, prepare blinded reports on adverse events, monitor study execution at clinical sites, and supply study medications to each site. The principal investigator of the Coordinating Center will serve as chair of the Steering Committee. The Coordinating Center will be blinded to treatment group during recruitment and follow-up in all trials. 2. The Statistical Center will be involved in study design, in planning and performing analysis, and prepare all summary reports to the Coordinating Center, Oversight Committee and NINDS-appointed Data and Safety Monitoring Board (DSMB). 3. Clinical Centers will recruit and follow participants, emphasizing participant adherence and the highest standards of protocol execution. Three representatives of Clinical Centers will be selected to participate on the Steering Committee. During the trial, Clinical Centers may be added, deactivated, or placed in a follow-up mode with budget reduction, depending on performance and recruitment requirements and requirements for protecting human subjects. In addition, there will be three key committees: 1. The Oversight Committee is organized by NINDS and includes NINDS clinical directors and program directors with expertise in pre-clinical science of neuroprotection and in clinical trials, together with extramural experts in PD and neurodegeneration, statistics, ethics, and representatives of PD advocacy groups. The Oversight Committee will give final approval to the agents to be tested, approve the final study design and plans for analysis developed by collaboration between the Steering committee. The oversight board may also evaluate and approve major protocol changes during the course of the trial in conjunction with the Data and Safety Monitoring Board (see below). The oversight board is composed of outside experts and NIH staff, who constitute approximately 25% of the members. 2. The Data and Safety Monitoring Board will monitor study execution and safety issues, and propose and consider interim analyses. It will be appointed by the NINDS and include a non-voting NINDS representative who will act independently of the NINDS Scientific Program Director (see below). This board will also evaluate and give final approval to any study modifications. 3. The Steering Committee will consist of the Coordinating Center Principal Investigator (who will chair the committee), the Principal Investigator of the Statistical Center, the NINDS Scientific Program Director, and three selected members drawn from the Clinical Centers. The Steering Committee will approve the protocols, supervise overall execution of the trial, generate and approve study policies, consider modifications of the protocol and operations, and plan and draft study- related publications. The NINDS scientific Program Director will function to expedite the activities outlined under Terms and Conditions (below), and serve as representative for the NINDS to the trial components. The NINDS Program Director will participate on the scientific committees of the trial, but she/he will not be responsible for fiscal management of the cooperative agreement, which will be done by a second NINDS program scientist. STUDY TIMETABLE It is anticipated that at least one large simple randomized, placebo- controlled clinical trial will be completed during the period of this initiative, although this depends on the results of the pilot trials. In addition, one or more pilot studies may be done for each of the proposed therapeutic agents to determine safety, dose, and feasibility parameters. Although the tentative timetable below indicates that multiple simultaneous pilot studies succeeded by one large simple clinical trial of multiple agents will be performed, the actual number and timing of protocols implemented may vary depending upon the specific study designs agreed upon. Years I-III (will be completed prior to the addition of new sites): o Drug selection, protocol development, recruitment, and follow-up for the first two pilot studies. Year IV: o Protocol development for the large-scale clinical trial will be ongoing and completed within 6 months of completion of the pilot trials. The manual of operations will be produced by the Coordinating Center in cooperation with the Statistical Center and Steering Committee. o Patient accrual will begin and continue for up to 30 months (or more) at an average rate of two patients per month per center. Year V: o Patient accrual and follow-up in the manner of a large simple trial. Year VI: o Patient accrual and follow-up in the manner of a large simple trial. Year VII: o Patient follow-up in the manner of a large simple trial for six months. o Start of the post-trial treatment for six months of placebo patients with selected treatments from the main phase of the trial (if necessary, depending on study design). This study after the completion of the main trial will require additional follow-up of patients in one or more arms of the trial. Year VIII: o End of the post-trial treatment for six months of placebo patients with selected drugs from the main phase of the trial. o Closeout, data audit, data analysis, and preparation of papers for publication will occur during this last year. Additional years may be required depending on the start date, the time required to complete the pilot studies, the rate of recruitment for the main trial, and the follow-up period needed. Should additional years be necessary, applicants will be required to submit a competitive renewal application. MECHANISM OF SUPPORT This RFA will use a NIH cooperative (U10) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. The anticipated award date is September, 2005. This RFA uses just-in-time concepts and the non-modular budgeting formats http://grants.nih.gov/grants/funding/modular/modular.htm). The NIH (U10) is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award." FUNDS AVAILABLE The number of centers funded under this solicitation is subject to the availability of funds at the time of award. NINDS may commit up to $1,200,000 in FY 2005 to fund as many as 12 new grants in response to this RFA, but may select a smaller number of centers based on the needs of the study, quality of applications, and availability of funds. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $ 73,500 per year. Because the nature and scope of the proposed research will vary from study to study, funds will be awarded based on expected recruitment and performance and future awards will be based on demonstrated recruitment and performance, measured on a per subject basis. It is anticipated, therefore, that the size and duration of each award will also vary from center to center. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations o Faith-based or community-based organizations. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS The intent of this RFA is to solicit applications from qualified investigators proposing to serve as Clinical Centers in order to conduct pilot trials and a large, collaborative randomized double-blind trial testing neuroprotective agents in patients with early PD. The final study design will be developed through collaboration between the Steering Committee and Oversight Committees. Special Requirements for Clinical Centers 1) A Clinical Center is an institution that is actively involved with the recruitment, evaluation, treatment and follow-up of study participants. It will consist of a team of researchers with the neurological skills to apply diagnostic criteria for PD and study selection criteria and to deliver medical care to PD patients and, optimally, with experience in collaborative clinical studies. It may have agreements to form a local network with other nearby institutions to recruit and treat patients for this study. 2) A Clinical Center will collaborate with other Clinical Centers and with the Coordinating Center, Statistical Center, and NINDS Scientific Program Director, to participate in the development of the pilot study and trial protocols, to recruit patients to participate in the trial, and to follow the protocol for each participating patient. Accurate and complete data reporting are paramount. Complete follow-up in a large simple trial will require innovative methodology since frequent patient contact will not be possible. Cooperation with patient advocacy groups is encouraged as a means for encouraging patient compliance and commitment to the trial. 3) A Clinical Center will attempt to identify and recruit all eligible patients with follow-up of participants according to the final, approved pilot study and trial protocols using standardized data collection procedures. 4) Each Clinical Center is currently required to recruit one participant per month during the for the pilot trials when de novo subjects are sought and it is expected that this will increase to two or more subjects per month during the main trial when the study population may be broadened to include patients on symptomatic therapies. A regional screening/recruitment strategy enlisting the support of PD advocacy groups may be necessary to achieve this goal at many sites. 5) A Clinical Center will participate in the cooperative design of study protocols and preparation of the manual of operations. 6) It is critical to the success of this project that each Clinical Center maintain contact with all recruited patients and carry-out complete, accurate data collection and timely transmission of the data to the Coordinating Center. To assure the overall quality of the pilot studies and trial Clinical Centers must cooperate with data audits and other quality control procedures established by the protocol, Steering Committee, and Data and Safety Monitoring Board. 7) A Clinical Center may participate on the Steering Committee and Publications Committee, according to the charter of the Steering Committee. 8) Each Clinical Center must agree to publish data collected from their site only in accordance with guidelines established by the Publications Committee. 9) Clinical Centers are required to take all appropriate measures to protect human subjects and ensure adequate representation of genders and racial/ethnic minorities. COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the notice of grant award. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH grant administration policies. The administrative and funding instrument used for this program is a cooperative agreement (U10), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NINDS scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NINDS purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NINDS Scientific Program Director and NINDS-appointed Oversight Committee as described below. 1) Awardees Rights and Responsibilities. The awardees for the Clinical Centers will: a) Participate in the design of the study protocols and the writing of the manual of operations for one the pilot studies and the large clinical trial; b) Help develop operational plans and carry out patient recruitment, treatment, and follow-up that is efficient; c) Carry out complete and accurate data collection and timely transmission of the data to the Coordinating Center; d) Suggest approaches to the analyses of data and participate in writing manuscripts of the interim and final results of the trial and pilot studies; e) Ensure adequate representation of women and racial/ethnic minority subjects in the pilot studies and phase III clinical trial; f) Willingly adhere to a common study protocol for each pilot study and the large trial; g) Take all appropriate measures to protect human subjects as required by DHHS regulations and NIH policy; h) Attend all training meetings and annual investigators’s meeting as outlined in the protocol; i) If placed on non-recruiting status due to deficiencies in performance, agree to continue follow-up of participants according to the protocol unless follow-up arrangements can be made through an alternate Clinical Center; j) Agree to publish data collected as part of the trial according to guidelines established by the Steering/Publications Committee; k) Carry out the other elements of the research project as described in this RFA. Awardees will retain custody of and primary rights to their data developed under the award, subject to government policies regarding rights of access. In accordance with the policies and procedures established by the Steering Committee, all Clinical Center awardees will be required to provide study data to the Coordinating Center. The Coordinating Center will, in turn, be required to transmit all data to the Statistical Center. The data will be stored at the end of the trial in a format suitable for archival in a United States national repository at a time when the investigators no longer have a use for the data. A plan for eventual placement in a national archive will be developed by the grantees and approved by the NINDS. 2) NINDS Responsibilities. The NINDS will assign a Scientific Program Director for the study, who will have substantial programmatic involvement that is above and beyond the normal programmatic stewardship, as described below. The Scientific Program Director’s function is to advise the Steering Committee, the Publication Committee, and other subcommittees in carrying out the trials, including quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and coordination of efforts of all the project centers. The NINDS Scientific Program Director has voting membership on the Steering Committee, and as appropriate, other subcommittees of the Steering Committee including the Publications Committee. To the extent that the NINDS Scientific Program Director contributes to the scientific content of the trial, authorship may be shared in publications with other investigators in accordance with the same policies of the Publication Committee that apply to other investigators. A second NINDS Program Director/Official administers the cooperative agreements and will be responsible for the normal programmatic and fiscal management and stewardship of the program at the NIH. Other NINDS scientists may, as appropriate, attend meetings and serve on study committees and work with awardees on issues coming before the Steering Committee or its subcommittees. However, in all cases, the NINDS will have only a single vote on each study committee. The NINDS has appointed and directly supports the travel and other expenses of a Data and Safety Monitoring Board. The NINDS reserves the right to terminate or curtail the study (or an individual award) in the event of (a) a major breach in the protocol or substantial changes in the agreed-upon protocol with which the Institute does not agree or (b) human subject ethical issues that may dictate a premature termination or (c) failure to pursue the objectives stated in this Request for Applications, or (d) substantial shortfall in recruitment and/or retention of subjects, or (e) a recommendation to the NINDS by the DSMB to stop a pilot study or the large trial. 3) Governance An Oversight Committee has been appointed by the NINDS. It does not include the NINDS Scientific Program Director who is a member of the Steering Committee. It includes the NINDS Associate Clinical Directors for Clinical Trials, an NINDS program scientist with expertise in pre- clinical research, outside experts in clinical research and statistics and Parkinson Disease, patient advocates, and an expert in ethics. Protocols, protocol modifications, and choice of interventional agents will be reviewed and approved by the Oversight Committee. Approximately 25% of the oversight board are NIH staff. The study will be governed by a Steering Committee. The Steering Committee is comprised of the Principal Investigators of the Coordinating Center and the Statistical Center, the NINDS Scientific Program Director, and three Principal Investigators from the Clinical Centers selected by the other members of the Steering Committee and approved by the Oversight Committee. Initial representation of the Clinical Centers on the Steering Committee will be based on the availability of expertise in relevant approaches to study design and selection of neuroprotective agents. After patient recruitment begins, membership from the Clinical Centers may rotate. Each member of the Steering Committee will have one vote, and all major scientific decisions will be determined by majority vote of the Steering Committee subject to approval by the NINDS Oversight Committee. The Chair of the Steering Committee will be the Principal Investigator of the Coordinating Center. The Steering Committee has primary responsibility for developing common clinical protocols and obtaining approval of the protocols by the NINDS Oversight Committee. They also facilitate the conduct and monitoring of the trials, and reporting the study results. The Steering Committee may appoint subcommittees to perform specific tasks; one will be a Publication Committee to establish publication policies and approve publications prior to submission. Subcommittees appointed by the Steering Committee and consisting of Principal Investigators and appropriate staff from the Clinical Centers, the Coordinating Center, and the Statistical Center will be involved in the design of the protocols and the manual of operations, and in ongoing functions of the trials, such as review of ancillary studies and preparation of publications. Not all Clinical Centers will necessarily be represented on all subcommittees. The NINDS Scientific Program Director may choose to participate in any of the meetings of these subcommittees. The Director, NINDS, has appointed an independent Data and Safety Monitoring Board, to review periodically the progress of the trials. It is comprised of experts in relevant medical, statistical, operational, and bioethics fields who are not otherwise involved in the study. The Data and Safety Monitoring Board will oversee participant safety, approve procedures for blinding, evaluate results, monitor data quality, and provide operational and policy advice to the NINDS in accordance with the policies and procedures of the NIH and the NINDS. The Principal Investigator of the Coordinating Center, the Principal Investigator of the Statistical Center, and the NINDS Scientific Program Director may be invited to attend Data and Safety Monitoring Board meetings. An NINDS representative will be present at all sessions of the meetings. 4) Arbitration. Any disagreement that may arise in scientific- programmatic matters between award recipients and NINDS may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NINDS not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NINDS, and a third member selected by the preceding two members. These special arbitration procedures in no way affect the awardee’s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulations at 45 CFR Part 16. The conditions of award will apply and have precedence in all disagreements unless mutually agreed by both NINDS and the awardee. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: Direct inquiries regarding scientific or programmatic issues to: Bernard Ravina, M.D. Clinical Trial Group National Institute of Neurological Disorders and Stroke Neuroscience Center 6001 Executive Blvd. Rockville, MD 20892 Telephone: (301) 496-9135 FAX (301) 480-1080 Electronic mail: ravinab@ninds.nih.gov Direct inquires regarding peer review matters to: Katherine Woodbury-Harris, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke Neuroscience Center Suite #3208 6001 Executive Blvd. Bethesda, MD 20892-9529 (For express/courier use Rockville, MD 20852) Tel.: (301) 496-5980 Fax: 301-402-0182 Electronic mail: harrisk@ninds.nih.gov Direct inquiries regarding fiscal matters to: Aaron Kinchen Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd. Rockville, MD 20892 Telephone: (301) 496-7386 FAX (301) 402-0219 Electronic mail: kinchena@ninds.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Scott Janis, PhD Clinical Research Program Manager National Institute of Neurological Disorders and Stroke Neuroscience Center Rockville, Maryland 20892 Telephone (301) 496-9135 FAX: (301) 480-1080 email: janiss@ninds.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms. Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The D&B number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. Telecommunications for the disabled: TTY 301-451-5936 USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to: Katherine Woodbury-Harris, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke Neuroscience Center Suite #3208 6001 Executive Blvd. Bethesda, MD 20892-9529 (For express/courier use Rockville, MD 20852) Tel.: (301) 496-5980 Fax: 301-402-0182 harrisk@ninds.nih.gov Special Instructions for Preparing Applications for a Clinical Center Within the Research Plan portions of the applications for the Clinical Centers, the following issues should be covered: o Clinical Centers must be capable of enrolling at least 2 PD patients per month, including newly diagnosed patients not requiring medication and patients recently on medication for PD. Applicants should provide documentation of the availability of PD patients who are early in the course of their disease, including women and racial/ethnic minorities. o Applicants should document availability and clinical research experience of the Clinical Center staff. Additionally, describe the measures that will be implemented to ensure the safety of study participants. o Applicants should describe the clinic environment where the study visits will be conducted. o Applicants should document prior involvement (if any) in single- center and multi-center clinical trials, including experience in recruiting and following PD patients and patients with other neurological disorders, and experience in completing data collection forms in an accurate and timely manner. o If the Clinical Center will be a consortium of local sites, applicants should describe the history of the consortium and how it will operate to ensure uniform patient care and compliance with the protocol. Additionally, describe the advantages of the collaboration in terms of cost and recruitment capabilities. o Clinical Centers must form alliances with PD patient advocates in their local areas in order to facilitate recruitment and follow-up of study participants. Applicants should document existing alliances or describe alliances they intend to establish. o Applicants should describe their plans for recruiting study participants, including women and racial/ethnic minorities, retaining them in the study, and encouraging them to adhere to the protocol. o Applicants must include an explicit statement of willingness to cooperate with the other centers in the conduct of one or more clinical trials testing agents approved by the Oversight and Steering Committees. o Clinical Center applicants are encouraged, but not required, to include creative ideas about study design and discussion of the issues surrounding neuroprotection trials in PD, as well as to propose and justify one or more neuroprotective agents for testing. APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NINDS. Incomplete and/or nonresponsive applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NINDS in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Advisory Neurological Disorders And Stroke Council. Review Criteria Applications will be judged on the basis of the ability of the investigators to fulfill the SPECIAL REQUIREMENTS for each component described in this RFA, comply with the cooperative agreement terms and conditions of award, and to attain the goals stated above in the RESEARCH OBJECTIVE section as demonstrated by the capability and expertise documented in the application. The specific review criteria are described below. The final design for the clinical trial will be developed collaboratively by the Steering Committee relying largely on the expertise of the Coordinating Center and the Statistical Center. The major role of the Clinical Centers is to recruit patients. The peer review group will therefore focus on evidence that the Clinical Center applicant can recruit sufficient patients and willingly accept the responsibility to meet or exceed all requirements for human subject protection. Recruitment Capability: Is there evidence of prior experience in the recruitment of Parkinson patients to clinical trials? Are there realistic plans for the recruitment of newly diagnosed patients and those early in the course of treated PD, including women and minority participants for the proposed clinical trial? Does the application provide credible estimates of recruitment capability supported by detailed data derived from the current population of Parkinson patients that demonstrate all of the characteristics required by the trial selection criteria (clinical diagnosis of PD, recent diagnosis soon after first symptoms develop, not taking drugs that induce Parkinsonism, absence of other disease likely to prevent 5-year follow- up. Patients may be recently started on dopaminergic treatment). Is there sufficient evidence based on prior experience in clinical trials, chart reviews, and from other documents that the center will be likely to recruit sufficient patients? If patient availability is limited at the primary institution, are there satisfactory agreements with other institutions or clinics in the same geographic area? If the recruitment plans include more than two clinical sites at one Clinical Center are adequate measures proposed to ensure uniform patient care and compliance with the protocol? Does the Clinical Center have evidence of the percentage of eligible Parkinson patients who have agreed to participate in previous trials? Are the advantages of collaboration in terms of cost and recruitment capabilities (including the recruitment of minorities and women) clearly described? Is the organizational/administrative plan for such arrangements clearly delineated and efficient? Retention Capabilities: Are there complete plans and/or experience in achieving high rates of follow-up of trial participants and promoting high levels of adherence to the protocol? Environment: Does the environment in which the work will be done contribute to the probability of success? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The reasonableness of the proposed budget and duration in relation to the proposed research. The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. The adequacy of the proposed plan to share data, if appropriate. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. SHARING RESEARCH DATA: It is expected that data will be submitted in a timely fashion to the coordination center. Additional data sharing may occur as part of this multi-center collaboration. Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing This requirement will apply for all applications received in response to this RFA, even though the direct costs requested will be less than the $500,000 threshold. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: December 23, 2004 Application Receipt Date: January 24, 2005 Peer Review Date: April, 2005 Council Review: May, 2005 Earliest Anticipated Start Date: September 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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