RTI International RTI International is a trade name of Research Triangle Institute. Guidance for Investigators NHLBI Grant Funding Application Process for the Multi-Site Clinical Trials (Collaborative R01) FOA Meeting of Investigators supported by the NHLBI Clinical Trials Pilot Studies (R34) and NHLBI Clinical Trials Planning Studies for Rare Thrombotic and Hemostatic Disorders (U34) program Diane Catellier, DrPH September 29, 2015

RTI International Overview  Funding Opportunity Announcements (FOA)  NIH policy for R01 applications that request – ≥ $500,000 or more in direct costs in any year – < $500,000 in direct costs in all years  Letter requesting approval to submit proposal  Meeting with NHLBI staff to discuss proposed full-scale trial  Collaborative R01 applications  International sites (“foreign component”)  Resubmissions 2

RTI International Funding Opportunity Announcement (FOA)  The NHLBI Clinical Trials Pilot Studies (R34) and Clinical Trials Planning Studies for Rare Thrombotic and Hemostatic Disorders (U34) initiatives provide support for investigators to address the gaps in scientific knowledge and refine their protocols prior to launching a full trial.  Program will allow for early identification of non-feasible trial concepts, and will increase the number of important R01 clinical trials that are successfully completed 3

RTI International Funding Opportunity Announcement (FOA)  Full-scale trial after R34/U34 support – NHLBI FOA PAR : Investigator Initiated Multi-Site Clinical Trials (Collaborative R01) files/PAR htmlhttp://grants.nih.gov/grants/guide/pa- files/PAR html – No commitment to funding – Maximum project period – 5 years  SF424 does not provide any provision for anything more than 5 years – FOA is due to be re-issued (expires May 8, 2016) 4

RTI International NIH policy for applications with direct costs ≥ $500K in any year  Any application requesting $500,000 or more in direct costs in any year must be accompanied by a letter from the NHLBI stating that it will accept the application. Details are available at – $500k limit applies to total budget – DCC, CCC, sites, (funds and value of goods or services provided by third-party contributors* must also be included)  Additional policies that apply to multicenter clinical trial grant applications available at 5

RTI International Steps in submitting an application with direct costs ≥ $500K in any year  Step 1 – Contact the program official of the expected funding division to engage in preliminary discussions of study plan, stage in protocol development, ballpark budget, anticipated application submission date, etc. – The program official will be the point of contact on all matters related to the request to submit an application requesting > $500K in direct costs in any given year 6

RTI International Steps in submitting an application with direct costs ≥ $500K in any year  Step 2 – Submit a letter of request, including budgetary information, to the funding division Director (via program official) requesting permission to submit an application with direct costs greater than $500K in any given year  The funding division considers the overall budget and will comment on scientific and administrative aspects  If approved, the study will be reviewed by the clinical trials review committee, which reviews all multisite clinical trial applications  Although the funding division will provide a critical review of feasibility to carry our the full scale trial, public health and clinical importance, much of that evaluation will be left to peer review 7

RTI International Steps in submitting an application with direct costs ≥ $500K in any year  Step 3 – Work with program official to schedule meeting with relevant NHLBI funding division staff (“staff visit”) to review the planned application – Can be in person or by teleconference – Opportunity to ask questions and get feedback on your proposed research and discuss submission and review issues 8

RTI International Timing of submission of the letter of request  The timing of letters of request seeking to submit grant applications of $500K or more in any year varies with the amount cost of the research project.  > $500K but less than $1,515,000 (PPG or program project grant cap) – requests can be made at any time during the year, but must be received by NHLBI no later than 6 weeks prior to submission date – 6 weeks prior to Feb, June, or Oct 5 th for new R01 applications – 6 weeks prior to Mar, July, or Nov 5 th for renewal R01 applications 9

RTI International Timing of submission of the letter of request  If the amount requested is > $1,515,000 – requests can only be made before two specific deadlines in each calendar year – November 15 th for an intended February 5 th submission date – May 15 th for an intended October 5 th submission date  Note: The PPG cap is subject to change. 10

RTI International Letter requesting approval to submit application  Letter should be not be longer than 5 pages and include: – sufficient information about the specific aims of the research (including subprojects) – significance and/or potential impact of the research on public health or health care of the research – annual direct, and total direct costs, and total costs – key investigators 11

RTI International Letter requesting approval to submit application  If duration of the trial is greater than 5 years, indicate in the letter and submit a budget for all years – Indicate need for more than 5-year period of funding in budget justification  Program officer can guide investigator further about what to include in the letter 12

RTI International Letter requesting approval to submit application  Review typically takes place within 1 month of receipt of request – If you wait to submit until 6 weeks prior to submission date, approval letter may arrive as close as 2 weeks prior to the submission date – try to get it in EARLIER.  NHLBI can accept/reject your application for review, or request modifications – May want to submit letter more than 6 weeks prior to submission date to allow time to address modifications – Acceptance is valid for up to 2 years, but only one resubmission (need to submit new request for a new submission) 13

RTI International Letter requesting approval to submit application  If NHLBI agrees to accept your application for review, you will receive a letter of approval – Letter will go to CCC and DCC institutions – Letter will have two budget caps: first year direct costs, and total direct costs for 5 years (excluding F&A costs) – Budget caps for direct costs in Year and all 5 years apply to the combined DCC/CCC, but can be distributed however you want 14

RTI International Letter requesting approval to submit application  Include a copy of approval letter with your application and refer to in a cover letter when it is submitted to the Center for Scientific Review (CSR) – If it is not attached, CSR will return the application and NHLBI will not intercede on your behalf 15

RTI International Meeting with NHLBI staff to discuss proposed full-scale trial  Ensure you are prepared to discuss: – Study Design and Methods  study population  eligibility, inclusion/exclusion criteria  enrollment plan, feasibility  primary and secondary endpoints  methods of randomization  sample size and power calculations  data collection and entry  schedule of visits  quality control procedures including training of study personnel  statistical analysis  study timeline 16

RTI International Meeting with NHLBI staff to discuss proposed full-scale trial  Ensure you are prepared to discuss: – Study Organization  verbal descriptions are necessary, but a flow chart or diagram of the study organization is a plus – Human Subjects  patient safety and confidentiality, informed consent, adverse event monitoring and reporting plan, ethical considerations, need for IND/IDE – Gender/Minority/Children (include prevalence estimates of study population and planned enrollment by subgroup) – Enrollment feasibility assessment (preliminary if not complete)  Consider sending PowerPoint slides in advance 17

RTI International Meeting with NHLBI staff to discuss proposed full-scale trial  The review panel may request that… – greater attention be provided to things such as adherence or endpoint definition that may have a bearing on the overall feasibility of the study – more data to support power calculations, recruitment, etc.  The meeting is meant to be a stage at which the investigator can preempt, or work through, potential problems – Probably no greater risk than not being able to meet recruitment goals. 18

RTI International Collaborative R01 applications  If the amount you are requesting is > $500K in direct costs in any year, you must plan to have a separate Data Coordinating Center (DCC) application  This application will be linked to the lead (Clinical Coordinating Center, CCC) application and reviewed together as one project  The Research Strategy section of the CCC or DCC application may not exceed 12 pages  If the amount you are requesting is < $500K, you must submit a single (12 page) application 19

RTI International Collaborative R01 applications  If needed, you may include an additional clustered application for a Core Lab or Imaging/Reading Center. – These clustered applications will be reviewed with the lead and DCC applications – Research Strategy should not exceed 6 pages  Each application in the cluster should include its own face page, budget, budget justification and biosketches  Each application in the cluster should have the same title (with “CCC” or “DCC” appended to title), and abstract 20

RTI International Collaborative R01 applications  Only the lead application should include the scientific background and significance sections  DCC and core applications need only describe their specific functions and do not need to repeat the science – They may, however, reference the science in the lead application 21

RTI International Collaborative R01 applications  Letters of commitment from enrollment sites, industry, consultants and other collaborators  Do not circumvent page limitations of the Research Strategy by including materials in the Appendix  CCC Appendix could include: – informed consent – clinical protocol – no more than 3 relevant published manuscripts (only when a free, online, publicly available journal link is not available) 22

RTI International Collaborative R01 applications  DCC Appendix could include: – Enrollment Feasibility Assessment – Data collection forms – Flow diagram describing the flow of participants through the various stages of the trial  Study organization and administration – Figure depicting organizational structure of the trial (NHLBI, committees, advisory group, DSMB, DCC, CCC) – Justification for Foreign Institution Involvement – Timetable for Completion of Key Milestones – Same in both applications 23

RTI International Collaborative R01 applications  Resource sharing plan – fleshed out in DCC application, can be referenced in CCC application  Protection of human subjects – DCC application can refer to Human Subjects section of the companion CCC application for details on human subjects research procedures and protections at the clinical centers – DCC application should refer to data collection and processing procedures to protect individual rights and to comply with all applicable laws and ethical principles  right to informed consent; right to decline participation, withdraw at any time, and refuse to answer any question; right to privacy. – Data and Safety Monitoring Plan 24

RTI International Resubmissions  Resubmission of application requires notification of program official of timing of resubmission (at least 6 weeks before submission deadline) – As long as budget does not change, you can use you original letter indication permission to submit the application – Limit is 37 months for resubmission 25