PARKINSON DISEASE NEUROPROTECTION CLINICAL TRIAL: CLINICAL CENTERS Release Date: July 2, 2001 RFA: RFA-NS-02-010 National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: September 15, 2001 Application Receipt Date: Nov 15, 2001 PURPOSE The Neurodegeneration and Clinical Trial Groups of the National Institute of Neurological Disorders and Stroke (NINDS) request applications for clinical centers to collaborate in the performance of a large, double-blind randomized trial of two or more potential neuroprotective agents in patients early in the course of Parkinson’s disease. Applications for coordinating and statistical centers were requested in a separate solicitation (http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-01-012.html). The trial was called for in the NIH Parkinson Research Agenda (http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm). The neuroprotectants to be tested in the trial have not yet been chosen and will be selected by an NINDS-appointed Oversight Committee from among those proposed by the applicants who respond to this Request for Applications (RFA) as well as from those suggested by others, including NINDS grantees, pharmaceutical companies, patients, and patient advocates. BACKGROUND Parkinson’s disease (PD) affects nearly a million Americans, a number that will increase over the coming decades. While available medical therapies are usually effective for controlling symptoms for the initial years following diagnosis, higher doses of multiple agents are required over time, with increasing side-effects and incomplete control of symptoms. While these treatments can dramatically improve the lives of patients with Parkinson’s disease initially, they have been based on dopamine replacement since the early 1970 s. They do not address the underlying disease cause or the currently inevitable biological progression of PD. The typical course of PD is one of gradual worsening over a decade or more, corresponding to ongoing neuronal loss affecting cells in the pigmented nuclei of the brain, particularly in the substantia nigra. There is a long preclinical phase preceding diagnosis, during which loss of these dopaminergic neurons progresses until the threshold for clinical symptoms is reached, estimated to be about 70-80% loss by the time of diagnosis. Given this prolonged course of progressive neuronal loss, strategies aimed at reducing the rates of neuronal loss or dysfunction (i.e. clinical neuroprotection or disease-modification) are particularly important in this disorder. Effective clinical neuroprotection would importantly reduce PD-related disability for hundreds of thousands of Americans, prompting the National Institute of Neurological Disorders and Stroke (NINDS) to invite qualified investigators to submit grant applications for components of a clinical trial aimed at identifying agents to slow the progression of PD. With many potential neuroprotective interventions available, clinical trial designs in which several agents are compared to a single control group have many advantages that may increase participant acceptance because 1) assignment to control is less likely and 2) there is the potential to compare directly the active interventions. Factorial designs in which some participants may receive more than one active intervention offer the further potential to assess effects of combinations of neuroprotective agents that may work by different mechanisms, (although statistical power to define interactions may be limited). By definition, large, simple clinical trials focus on limited goals and a few key outcomes supplementing such streamlined protocols, subsets of participants in large, simple trials at selected sites can be more intensively investigated. Despite the substantial disability due to PD, few interventional studies have evaluated agents that might retard disease progression. A previous investigator-initiated trial supported by NINDS, Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), evaluated selegiline (Deprenyl) and vitamin E as treatments for PD. Vitamin E was found ineffective, and selegiline has not become widely used because of uncertainty about a neuroprotective vs. symptomatic effect due to an initially unsuspected dopa-agonist action. The Parkinson Agenda for the NIH was published in April, 2000 (http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm). The agenda calls for the initiation of randomized controlled clinical trials to test potential neuroprotectants. Expert advice regarding implementation of this initiative was solicited at the meeting Therapeutic Initiatives in Parkinson Disease convened by the NINDS (13-Oct-00, Bethesda), which included representatives of several NIH Institutes and national experts in PD and clinical research in neurodegenerative disorders. RESEARCH OBJECTIVE To demonstrate convincingly in a randomized, double-blind clinical trial the efficacy of one or more pharmacological agents for slowing progression of PD and to determine the toxicity and tolerability of these agents. Design of a clinical neuroprotection trial. Final design of the clinical trial will result from collaboration between and consensus of the Coordinating Center, NINDS scientific staff, the Statistical Center, Principal Investigators from Clinical Centers, and the NINDS Oversight Committee (see Study Organization, below). It is anticipated that key elements of the trial will include the following: 1) Inclusion of PD patients early after clinical diagnosis with two of the four cardinal signs, not taking drugs that induce Parkinsonism, absence of other disease likely to prevent 5-year follow-up. Patients have recently started dopaminergic treatment. 2) Design capable of detection of small treatment effects because of the clinical importance of even modest benefits to PD patients. 3) General design as a large, simple trial, including large sample size (about 3000 participants), infrequent regular follow-up, and limited data collection, focusing on functional and disability-related outcomes, including those that can be assessed without direct patient contact using either mail or telephone. 4) Prospective plans to distinguish neuroprotective effects from occult symptomatic benefits. The trial will involve the following phases: 1) Selection of potential neuroprotective agents. 2) Pilot studies to develop dose and safety information, to select pharmaceutical agents useful for the main trial, and to refine outcome measures (approximately one year). 3) Main multi-arm trial (approximately 6 years). 4) If necessary, post-trial administration of one or more apparently efficacious neuroprotective agents to all participants to assess occult symptomatic effects and convincingly establish neuroprotection (six months to one year). The entire trial may last up to eight years. Participants in the trial will be enrolled in the earliest stages of the disease possible, and may or may not require symptomatic therapies (depending on the final approved study design). Based on observations from the initial and second randomization in the DATATOP trial, it is anticipated that there will be measurable evidence of disease progression during follow-up averaging three to four years (extending to five years in some participants), both in those receiving dopaminergic agents and those who are not. Outcome instrument development and/or adaptation of existing instruments for use with a large, simple trial design is a key objective of the pilot phase. Use of disability and functional outcome scales sensitive to changes seen during the early course of PD will be emphasized as the primary outcomes. Effects on non-motor features will be included. Available biomarkers have not been appropriately validated to substitute for clinical outcomes in the large phase III. Assessment of biomarkers for screening and in selection of neuroprotective agents will be considered. Since biomarkers as surrogate outcomes require validation by correlation with clinical outcomes in positive clinical trials, the concomitant assessment of biomarkers in the large neuroprotection trial, particularly at selected centers or patient subsets, will also be considered, balancing expense and complexity with the overall goals of the large trial. Several candidate agents for neuroprotection testing will likely emerge from this RFA. Because even a small neuroprotective effect with a minimally toxic agent would be important to detect, a relatively large trial is required. Minimizing the cost for each participant will permit larger numbers of participants and make it possible to evaluate more potential neuroprotective agents. The boundary presented by large sample sizes and the cost of conventional studies needs to be crossed in order to obtain the initial success required to sustain research of further neuroprotective treatments. Detecting small effects requires large sample sizes, but it does not mandate a complex protocol. Rather, intermediate contact by mail or telephone, allowing less frequent clinical contact, may provide the needed data at many time points, and reduce costs. It is anticipated that highly reliable functional outcome or disability scales that are multi-modal can be included to simplify outcome measures and reduce the cost of the trial. Several design issues common to large, simple trials must be considered and addressed. Compliance is a major concern, particularly if one or more of the treatments being tested is generally available either over- the-counter or through prescription. Dropouts and patients lost to follow-up must be minimized. Inexpensive methods to maintain patient loyalty and protocol adherence between infrequent clinic visits will be important for successful execution. Reliable outcome measures assessed by different clinicians and other medical professionals are necessary, since primary care providers may have more ready access to a patient than the neurologist. It may also be helpful to enlist the support of PD patient advocacy groups to help build and maintain patient loyalty. Rapid recruitment and initiation of treatment are essential, facilitated by limited inclusion/exclusion criteria. Limited exclusion criteria will expose a broad spectrum of PD patients to the selected neuroprotective drugs, a likely advantage in the initial clinical trials. (When the characteristics that predict a patient’s response to a particular drug are not known, the chances of detecting any effect increase if there is a wide spectrum of PD patients participating in the study.) If neuroprotective effects are detected, further studies may then define appropriate selection criteria. Participants will reflect the gender and racial/ethnic composition of U.S. citizens with PD. Pilot data to determine the maximum safe dose for PD patients is not likely to be available for all agents to be tested, and a pilot study may be needed for most agents. Pilot trials should determine dose, safety, assess the presence of a dopaminergic effect, and refine/test outcome measures. These pilot studies may be critical to the eventual success of the subsequent large, definitive trial. Consequently, an initial pilot phase for testing each of the agents will be available as part of the planning phase for the trial. STUDY ORGANIZATION The organizational structure will consist of the following components: 1. The Coordinating Center will develop and manage the protocol, assure compliance with regulations, supervise and encourage recruitment, collect, store, and maintain data from clinical centers including recruitment and dropout data, prepare blinded reports on adverse events, monitor study execution at clinical sites, and supply study medications to each site. The principal investigator of the Coordinating Center will serve as chair of the Steering Committee. The Coordinating Center will be blinded to treatment group during recruitment and follow-up in all trials. 2. The Statistical Center will be involved in study design, in planning and performing analysis, and prepare all summary reports to the Coordinating Center, Oversight Committee and NINDS-appointed Data and Safety Monitoring Board (DSMB). 3. Clinical Centers (initially 42 sites) will recruit and follow participants, emphasizing participant adherence and the highest standards of protocol execution. Representatives of Clinical Centers will selectively participate on the Steering Committee. During the trial, Clinical Centers may be added, deactivated, or placed in a follow-up mode with budget reduction, depending on performance and recruitment requirements and requirements for protecting human subjects. In addition, there will be three key committees: 1. The Oversight Committee will be organized by the NINDS and include NINDS clinical directors and program directors with expertise in preclinical science of neuroprotection and in clinical trials, together with extramural experts in PD and neurodegeneration and with representatives of PD advocacy groups. The Oversight Committee will give final approval to the agents to be tested, approve the final study protocol and plans for analysis developed by collaboration between the Coordinating Center and Statistical Center, and evaluate and approve all protocol changes during the course of the trial. 2. The Data and Safety Monitoring Board will monitor study execution and safety issues, and propose and consider interim analyses. It will be appointed by the NINDS and include a non-voting NINDS representative who will act independently of the NINDS Scientific Program Director (see below). 3. The Steering Committee will consist of the Coordinating Center principal investigator (who will chair the committee), the Principal Investigator of the Statistical Center, the NINDS Scientific Program Director, and selected members drawn from the Clinical Centers. The specific membership and charter of the Steering Committee will be proposed by the Coordinating Center and approved by the Oversight Committee. The Steering Committee will approve the final protocols, supervise overall execution of the trial, generate and approve study policies, consider modifications of the protocol and operations, and plan and draft study-related publications. The NINDS will name a Program Director whose function will be to expedite the activities outlined under Terms and Conditions (below), and serve as representative for the NINDS to the trial components. The NINDS Program Director will participate on the scientific committees of the trial, but she/he will not be responsible for fiscal management of the cooperative agreement, which will be done by a second NINDS program scientist. STUDY TIMETABLE It is anticipated that one large simple randomized, placebo-controlled clinical trial will be completed during the 8 year period of this initiative. In addition, one or more pilot studies may be done for each of the proposed therapeutic agents to determine safety, dose, and feasibility parameters. Although the tentative timetable below indicates that multiple simultaneous pilot studies succeeded by one large simple clinical trial of multiple agents will be performed, the actual number of protocols implemented may vary depending upon the specific study designs agreed upon. Year I: o Protocol development for pilot studies (3 months). o Patient recruitment and follow-up for several simultaneous pilot studies (6 to 9 months). Up to 12 patients per Clinical Center (n=42) will be recruited (total 504). o Protocol development for the large-scale clinical trial will be ongoing for an entire year and completed with a full manual of operations during the last three months of the first year. The manual of operations will be produced by the Coordinating Center in cooperation with the Statistical Center. Year II: o Patient accrual will begin at 42 centers and continue for 36 months at an average rate of two patients per month per center (total = 3024 participants). Year III: o Patient accrual and follow-up in the manner of a large simple trial. Year IV: o Patient accrual and follow-up in the manner of a large simple trial. Year V: o Patient follow-up in the manner of a large simple trial. Year VI: o Patient follow-up in the manner of a large simple trial. Year VII: o Patient follow-up in the manner of a large simple trial for six months. o Start of the post-trial treatment for six months of placebo patients with selected treatments from the main phase of the trial (if necessary, depending on study design). This study after the completion of the main trial will require additional follow-up of patients in one or more arms of the trial. Year VIII o End of the post-trial treatment for six months of placebo patients with selected drugs from the main phase of the trial. o Closeout, data audit, data analysis, and preparation of papers for publication will occur during this last year. Additional years may be required depending on the start date, the time required to complete the pilot studies, and the rate of recruitment for the main trial. SPECIAL REQUIREMENTS The intent of this RFA is to solicit applications from qualified investigators proposing to serve as Clinical Centers in order to conduct a large, collaborative randomized double-blind trial testing neuroprotective agents in patients with early PD. The final study design will be developed through collaboration between the Oversight Committee, Coordinating Center, NINDS Scientific Program Director, and Statistical Center. -- Special Requirements for Clinical Centers A Clinical Center is an institution that is actively involved with the recruitment, evaluation, treatment and follow-up of study participants. It will consist of a team of researchers with the neurological skills to apply diagnostic criteria for PD and study selection criteria and to deliver medical care to PD patients and, optimally, with experience in collaborative clinical studies. It may have agreements to form a local network with other nearby institutions to recruit and treat patients for this study. A Clinical Center will collaborate with other Clinical Centers and with the Coordinating Center, Statistical Center, and NINDS Scientific Program Director, to participate in the development of the pilot study and trial protocols, to recruit patients to participate in the trial, and to follow the protocol for each participating patient. Accurate and complete data reporting are paramount. Complete follow-up in a large simple trial will require innovative methodology since frequent patient contact will not be possible. Cooperation with patient advocacy groups is encouraged as a means for encouraging patient compliance and commitment to the trial. A Clinical Center will attempt to identify and recruit all eligible patients with follow-up of participants according to the final, approved pilot study and trial protocols using standardized data collection procedures. Each Clinical Center is required to recruit two participants per month during the recruitment phases of the pilot (6 months) and main (36 months) trials. A regional screening/recruitment strategy enlisting the support of PD advocacy groups may be necessary to achieve this goal at many sites. A Clinical Center will participate in the cooperative design of study protocols and preparation of the manual of operations. It is critical to the success of this project that each Clinical Center maintain contact with all recruited patients and carry-out complete, accurate data collection and timely transmission of the data to the Coordinating Center. To assure the overall quality of the pilot studies and trial Clinical Centers must cooperate with data audits and other quality control procedures established by the protocol, Steering Committee, and Data and Safety Monitoring Board. A Clinical Center may participate on the Steering Committee and Publications Committee, according to the charter of the Steering Committee. Each Clinical Center must agree to publish data collected from their site only in accordance with guidelines established by the Publications Committee. Clinical Centers are required to take all appropriate measures to protect human subjects and ensure adequate representation of genders and racial/ethnic minorities. TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the notice of grant award. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH grant administration policies. 1) Collaborative Responsibilities. The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NINDS scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NINDS purpose is to support and/or stimulate the recipient"s activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NINDS Program Director and NINDS-appointed Oversight Committee. The study will be lead by a Steering Committee. Members of this Committee will include the Principal Investigators of the Coordinating Center and Statistical Center, and the NINDS Scientific Program Director. After Clinical Centers are activated, the Principal Investigators of two Clinical Centers will be chosen by the other three members and approved by the Oversight Committee. The chair of the Steering Committee will be the Principal Investigator of the Coordinating Center. The Steering Committee may appoint subcommittees to perform specific tasks, one will be a Publication Committee to establish publication policies and approve publications prior to submission. 2) Awardees Rights and Responsibilities. The awardees for the Clinical Centers will: a) Participate in the design of the study protocols and the writing of the manual of operations for one or more of the pilot studies and the large clinical trial, b) Help develop operational plans and carry out patient recruitment, treatment, and follow-up that is efficient, c) Carry out complete and accurate data collection and timely transmission of the data to the Coordinating Center, d) Suggest approaches to the analyses of data and participate in writing manuscripts of the interim and final results of the trial and pilot studies, e) Ensure adequate representation of women and racial/ethnic minority groups in the pilot studies and trial, f) Willingly adhere to a common study protocol for each pilot study and the large trial, g) Take all appropriate measures to protect human subjects, setting a superior example in this regard for others to follow in the future, h) Attend all training meetings and annual investigator’s meeting as outlined in the protocol, i) If placed on non-recruiting status due to deficiencies in performance, agree to continue follow-up of participants according to the protocol unless follow-up arrangements can be made through an alternate Clinical Center, j) Agree to publish data collected as part of the trial according to guidelines established by the Steering/Publications Committee, k) Carry out the other elements of the research project as described in this RFA. Awardees will retain custody of and primary rights to their data developed under the award, subject to government policies regarding rights of access. In accordance with the policies and procedures established by the Steering Committee, all Clinical Center awardees will be required to provide study data to the Coordinating Center. The Coordinating Center will, in turn, be required to transmit all data to the Statistical Center. The data will be stored at the end of the trial in a format suitable for archival in a United States national repository at a time when the investigators no longer have a use for the data. A plan for eventual placement in a national archive will be developed by the grantees and approved by the NINDS. 3) NINDS Responsibilities. The NINDS will name the Scientific Program Director for the study. The Program Director’s function will be to advise the Steering Committee, the Publication Committee, and other subcommittees in carrying out the trials, including quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and coordination of efforts of all the project centers. The NINDS Program Director will have voting membership on the Steering Committee, and as appropriate, other subcommittees of the Steering Committee including the Publications Committee. To the extent that the NINDS Scientific Program Director contributes to the scientific content of the trial, authorship may be shared in publications with other investigators in accordance with the same policies of the Publication Committee that apply to other investigators. A second NINDS Program Scientist will administer the cooperative agreements and will be responsible for the fiscal management of the program at the NIH. Other NINDS scientists may, as appropriate, attend meetings and serve on study committees and work with awardees on issues coming before the Steering Committee or its subcommittees. However, in all cases, the NINDS will have only a single vote on each study committee. The NINDS will appoint and support the travel and other expenses of a Data and Safety Monitoring Board, either directly or through a supplement to the Coordinating Center grant. The NINDS reserves the right to terminate or curtail the study (or an individual award) in the event of (a) a major breach in the protocol or substantial changes in the agreed-upon protocol with which the Institute does not agree or (b) human subject ethical issues that may dictate a premature termination or (c) failure to pursue the objectives stated in this Request for Applications, or (d) substantial shortfall in recruitment and/or retention of subjects, or (e) a recommendation to the NINDS by the DSMB to stop a pilot study or the large trial. 4) Governance An Oversight Committee will be appointed by the NINDS. It will not include the NINDS Scientific Program Director who is a member of the Steering Committee or members from the same institution as any Center in the project. It will include the NINDS Associate Clinical Directors, an NINDS program scientist with expertise in pre-clinical research, outside experts in clinical research and Parkinson Disease, patient advocates and an expert in ethics. Protocols, protocol modifications, and choice of interventional agents will be reviewed and approved by the Oversight Committee. The Steering Committee will comprise the Principal Investigators of the Coordinating Center and the Statistical Center, the NINDS Scientific Program Director, and two Principal Investigators from the Clinical Centers selected by the other members of the Steering Committee and approved by the Oversight Committee. Initial representation of the Clinical Centers on the Steering Committee will be based on the availability of expertise in relevant approaches to study design and selection of neuroprotective agents. After patient recruitment begins, membership from the Clinical Centers will rotate and be based on recruitment and execution. The Steering Committee will have primary responsibility for developing common clinical protocols and obtaining approval of the protocols by the NINDS Oversight Committee. They will also facilitate the conduct and monitoring of the trials, and reporting the study results. Each member of the Steering Committee will have one vote, and all major scientific decisions will be determined by majority vote of the Steering Committee subject to approval by the NINDS Oversight Committee. The Chair of the Steering Committee will be the Principal Investigator of the Coordinating Center. The Oversight Committee must approve all protocol changes. Steering Committee meetings will most often take place via teleconference call, at least every six months. Subcommittees appointed by the Steering Committee and comprised of Principal Investigators and appropriate staff from the Clinical Centers, the Coordinating Center, and the Statistical Center will be involved in the design of the protocols and the manual of operations, and in ongoing functions of the trials, such as review of ancillary studies and preparation of publications. Not all Clinical Centers will necessarily be represented on all subcommittees. The NINDS Program Director may choose to participate in any of the meetings of these subcommittees. The Director, NINDS, will appoint an independent Data and Safety Monitoring Board, to review periodically the progress of the trials. It will be comprised of experts in relevant medical, statistical, operational, and bioethics fields who are not otherwise involved in the study. The Data and Safety Monitoring Board will oversee participant safety, approve procedures for blinding, evaluate results, monitor data quality, and provide operational and policy advice to the NINDS in accordance with the policies and procedures of the NIH and the NINDS. The Principal Investigator of the Coordinating Center, the Principal Investigator of the Statistical Center, and the NINDS Scientific Program Director may be invited to attend Data and Safety Monitoring Board meetings. An NINDS representative will be present at all sessions of the meetings. 5) Arbitration. Any disagreement that may arise in scientific- programmatic matters between award recipients and NINDS may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NINDS not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NINDS, and a third member selected by the preceding two members. These special arbitration procedures in no way affect the awardee’s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulations at 45 CFR Part 16. The conditions of award will apply and have precedence in all disagreements unless mutually agreed by both NINDS and the awardee. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. The total project period for applications submitted in response to the present RFA may not exceed five years. The earliest anticipated award date is July 1, 2002. This is a one time solicitation for applications. In order to complete the eight-year project to be proposed in response to this RFA, competitive renewal applications will be solicited for peer review from the successful applicants four years after the project starts in order to facilitate continuous funding beyond five years. The number of awards to be made and level of support to be provided depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the National Institute of Neurological Disorders and Stroke, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. FUNDS AVAILABLE It is expected that approximately $4,321,800 total cost (direct plus Facilities and Administrative costs) will be available each year over a five year period for all of the Clinical Centers. It is anticipated that 42 awards for Clinical Centers will be made for an average over the entire trial of $73,500 direct costs per year. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, clinics, laboratories, units of State and Local governments, and eligible agencies of the Federal Government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. INQUIRIES Written, including electronic mail, and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific or programmatic issues to: Bernard Ravina, M.D. Clinical Trial Group National Institute of Neurological Disorders and Stroke Neuroscience Center 6001 Executive Blvd. Rockville, MD 20892 Telephone: (301) 496-9135 FAX (301) 480-1080 Electronic mail: ravinab@ninds.nih.gov Direct inquiries regarding fiscal matters to: Gladys Bohler Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd. Rockville, MD 20892 Telephone: (301) 496-9231 FAX (301) 402-0219 Electronic mail: bohlerg@ninds.nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by September 15, 2001, a letter of intent that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information allows NINDS staff to estimate the potential review workload and to avoid conflict of interest in the review. The Letter of Intent is to be sent to: Scott Janis, PhD Program Analyst National Institute of Neurological Disorders and Stroke Neuroscience Center Rockville, Maryland 20892 Telephone (301) 496-9135 FAX: (301) 480-1080 email: janiss@ninds.nih.gov SCHEDULE SUMMARY Letter of Intent: September 15, 2001 Application Receipt Date: Nov 15, 2001 Scientific Peer Review: Approximately March, 2002 Review by NINDS Advisory Council: May 2002 Earliest Anticipated Award Date: July 1, 2002 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these awards. These forms are available at most institutional offices of sponsored research, from the Grants Information Office, Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, 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/labels.pdf. Please note this is in pdf format. Submit a signed, original of the application, including the Checklist, and three signed photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive Room 1040 MSC-7710 Bethesda, MD 20892-7710 (For express/courier use Bethesda, MD 20817) At the time of submission, two additional copies of the application must also be sent to: Lillian M. Pubols, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke Neuroscience Center Suite #3208 6001 Executive Blvd. Bethesda, MD 20892-9529 (For express/courier use Rockville, MD 20852) Tel.: 301-496-9223 Fax: 301-402-0182 e-mail: LP28E@NIH.GOV Applications must be received by Nov 15, 2001. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. --Special Instructions for Preparing Applications for a Clinical Center Within the Research Plan portions of the applications for the Clinical Centers, the following issues should be covered: o Clinical Centers must be capable of enrolling at least 84 participants in three and a half years for the pilot studies (n=12) and the main clinical trial (n=72). Applicants should provide documentation of the availability of PD patients who are early in the course of their disease, including women and racial/ethnic minorities. o Applicants should document availability and clinical research experience of the Clinical Center staff. Additionally, describe the measures that will be implemented to ensure the safety of study participants. o Applicants should describe the clinic environment where the study visits will be conducted. o Applicants should document prior involvement (if any) in single- center and multi-center clinical trials, including experience in recruiting and following PD patients and patients with other neurological disorders, and experience in completing data collection forms in an accurate and timely manner. o If the Clinical Center will be a consortium of local sites, applicants should describe the history of the consortium and how it will operate to ensure uniform patient care and compliance with the protocol. Additionally, describe the advantages of the collaboration in terms of cost and recruitment capabilities. o Clinical Centers must form alliances with PD patient advocates in their local areas in order to facilitate recruitment and follow-up of study participants. Applicants should document existing alliances or describe alliances they intend to establish. o Applicants should describe their plans for recruiting study participants, including women and racial/ethnic minorities, retaining them in the study, and encouraging them to adhere to the protocol. o Applicants must include an explicit statement of willingness to cooperate with the other centers in the conduct of one or more clinical trials testing agents approved by the Oversight and Steering Committees. o Clinical Center applicants are encouraged, but not required, to include creative ideas about study design and discussion of the issues surrounding neuroprotection trials in PD, as well as to propose and justify one or more neuroprotective agents for testing. Please see the Review Considerations. Budget Instructions for Clinical Centers: The maximal budget is $73,500 direct costs per year for each Clinical Center, to include salary support for a research nurse coordinator, physician investigator(s) participation, required travel to training workshops and annual investigator’s meetings ($1500 per year maximum), and all other required activities. Receipt of the full award amount is contingent upon recruitment of 2 participants per month during the 9 month pilot phase (n=12) and in the three-year main trial recruitment period (n=72) with successful protocol execution (attempted recruitment of all eligible patients, timely and complete follow-up and data collection, adequate protocol adherence, no participant lost-to-follow-up). Clinical Centers that do not participate in individual protocols or that do not meet recruitment/execution standards will have the grant budget reduced. For situations in which applicants have existing ongoing clinical research in PD, the scientific and budgetary implications of potential overlap should be described. If a center is capable of doing excellent research but able to provide fewer or more patients than requested, then such applications are welcomed. The requested budgets should be modified in proportion to the proposed number of patients. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NINDS. Incomplete or unresponsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NINDS in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Institute of Neurological Disorders and Stroke Advisory Council. Review Criteria Applications will be judged on the basis of the ability of the investigators to fulfill the SPECIAL REQUIREMENTS for each component described in this RFA, comply with the cooperative agreement terms and conditions of award, and to attain the goals stated above in the RESEARCH OBJECTIVE section as demonstrated by the capability and expertise documented in the application. The specific review criteria are described below. The final design for the clinical trial will be developed collaboratively by the Steering Committee relying largely on the expertise of the Coordinating Center and the Statistical Center. The major role of the Clinical Centers is to recruit patients. The peer review group will therefore focus on evidence that the Clinical Center applicant can recruit sufficient patients and willingly accept the responsibility to meet or exceed all requirements for human subject protection. Recruitment Capability: Is there evidence of prior experience in the recruitment of Parkinson patients to clinical trials? Are there realistic plans for the recruitment of patients, including women and minority participants for the proposed clinical trial? Does the application provide credible estimates of recruitment capability supported by detailed data derived from the current population of Parkinson patients that demonstrate all of the characteristics required by the trial selection criteria (clinical diagnosis of PD, recent diagnosis soon after first symptoms develop, not taking drugs that induce Parkinsonism, absence of other disease likely to prevent 5-year follow-up. Patients may be recently started on dopaminergic treatment). Is there sufficient evidence based on prior experience in clinical trials, chart reviews, and from other documents that the center will be likely to recruit sufficient patients? If patient availability is limited at the primary institution, are there satisfactory agreements with other institutions or clinics in the same geographic area? If the recruitment plans include more than two clinical sites at one Clinical Center are adequate measures proposed to ensure uniform patient care and compliance with the protocol? Does the Clinical Center have evidence of the percentage of eligible Parkinson patients who have agreed to participate in previous trials? Are the advantages of collaboration in terms of cost and recruitment capabilities (including the recruitment of minorities and women) clearly described? Is the organizational/administrative plan for such arrangements clearly delineated and efficient? Retention Capabilities: Are there complete plans and/or experience in achieving high rates of follow-up of trial participants and promoting high levels of adherence to the protocol? Environment: Does the environment in which the work will be done contribute to the probability of success? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The reasonableness of the proposed budget and duration in relation to the proposed research. The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. The adequacy of the proposed plan to share data, if appropriate. AWARD CRITERIA It is anticipated that the earliest award date will be July 1, 2002. Applications recommended by the National Institute of Neurological Disorders and Stroke Advisory Council will be considered for award based upon (a) scientific and technical merit, (b) program balance, and (c) availability of funds. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Parkinson Disease Neuroprotection Clinical Trial: Clinical Centers , is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.853. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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