Obstetric Pharmacology Research Units RFA-HD-09-002

1. Obstetric Pharmacology Research Units RFA-HD-09-002 Pre-Application Meeting February 11, 2009 Zhaoxia Ren, MD, PhD Obstetric and Pediatric Pharmacology Branch, CRMC, NICHD

2. NICHD OPRU Network • Background • Established in 2004 • Co-funded by ORWH under cooperative agreement (U10) • Unique Structure of the OPRU Network • Differs from most other NICHD-supported networks • Requires pairing a clinical Principal Investigator (PI) with a basic science co-PI to facilitate the translational nature of the work • Multidisciplinary collaborations across the network • Four institutions awarded during the initial funding cycle • University of Washington • University of Texas Medical Branch at Galveston • University of Pittsburgh • Georgetown University • Current ongoing studies/activities • Glyburide – study PK, PD, placental transport and metabolism of the drug in human and non-human pregnancies with gestational diabetes • 17-a Hydroxyprogesterone Caproate – understand the metabolism, PK, PD and potential mechanisms of action of this drug in preventing and decreasing the risk of preterm birth

3. NICHD OPRU Network • Mission • Provide the infrastructure needed to conduct basic, translational and clinical pharmacological studies that will help clinicians protect the health of women, while improving birth outcomes and reducing infant mortality • Goals • Identify, study and characterize drugs that are of therapeutic value during pregnancy and whose disposition and response are altered by the pregnant state in normal and abnormal pregnancies • Conduct multi-site cooperative clinical studies that advance the knowledge of PK and PD of drugs used during pregnancy • Conduct pharmacogenomics studies of the effects of pregnancy on drug delivery and action on the mother as well as on the developing fetus • Perform studies of placental transfer of drugs • Facilitate translational research so that clinical materials can be utilized for basic research studies • Enhance the exchange of information among basic scientists, neonatologists, and obstetricians • Serve as a resource for training health care providers in the field of obstetric pharmacology

4. OPRU RFA: HD-09-002 • The NICHD invites applications to participate in the OPRU Network to conduct pharmacologic studies of drug disposition and effect during normal and abnormal pregnancies • The NICHD intends to commit approximately $5 million in total cost in FY2010 to fund up to 5 new and/or competing continuation grants • An applicant may request a project period of up to five years and a budget for direct cost including the core/base costs and the study proposal costs up to $650,000 per year

5. OPRU RFA: HD-09-002 • Funding Mechanism: this RFA will use the NIH Cooperative Clinical Research (U10) award mechanism • More than one PD/PI may be designated on the application • Individual applicants may not submit more than one application in response to this RFA • Resubmissions are permitted in response to this RFA.

6. OPRU Network Organization • Steering Committee • (SC) • PIs • NICHD • DCAC Data Safety and Quality Monitoring Board (DSMB) Data Coordinating and Analysis Center (DCAC) • Sub-Steering Committees • Protocol Development • Data Analysis • Quality Control • Publication

7. Components of an OPRU Site • Pharmacology Component • Conduct PK and PD analysis • Conduct Pharmacogenetics/Pharmacogenomics Studies • Involve Phase I and II studies of existing or new molecular entities (NMEs) designed to treat pregnancy conditions/diseases • Clinical Study Component • Test drug disposition, efficacy, safety and toxicity in pregnant women including normal and abnormal pregnancy • Study efficacy of existing or new NMEs • Basic/Non-Clinical Research Component • Study basic mechanisms for differences in disposition of drugs and differences in response during normal and abnormal pregnancies

8. OPRU Sites Required to participate in a cooperative and interactive manner with one another and with DCAC OPRU PIs Required to participate in SC meetings, site visits, and regular teleconferences Cooperate with other PIs in the network in developing and designing research protocols Comply with study policies and quality assurance approved by the SC Transmit study data to the DCAC in a timely and accurate manner Report all adverse events in accordance with procedures established by the SC and NICHD policies Cooperate with other PIs in the network in publishing the study results and eventually releasing study procedures and other resources to the scientific community OPRU Network

9. Special Requirements • Principal Investigator (PI) • Overall management of the clinical pharmacology component • Coordination of the participating specialists whether within a single institution/a consortium of institutions • Design and submission of proposed protocols for pharmacologic studies, • Implementation and monitoring of the clinical studies, and submission and analysis of study data • Basic/pre-Clinical Investigators • Coordination of the OPRU basic/pre-clinical research • Development of adjunct basic/pre-clinical studies in cooperation with clinicians • Conduct of basic studies in conjunction with ongoing clinical trials/studies • Collaboration and sharing of basic resources and reagents within an OPRU site and with other OPRU sites

10. Eligibility Requirements • Principal Investigator (PI) • MD or PhD or PharmD • Collective experience in obstetrics, PK, PD, and drug metabolism • Experience in multidisciplinary research collaboration • Experience in writing clinical study protocols • Experience in clinical study design and conducting clinical trials • Accessibility to the appropriate population of subjects for such studies and ability or success in patient recruitment

11. Submission Instructions • Applications must be prepared using the most current PHS 398 research grant application instructions and forms • Special instructions on page limit • Overall page limit for Research Plan is 40 pages • 20 pages for the description of the OPRU unit infrastructure and capabilities • 20 pages for research concept proposals

12. Other Submission Requirements • Research Concept Proposals • Submit at least one clinical proposal and one basic/translational research proposal for a potential OPRU study • The proposal should include: specific aims, background /significance, preliminary studies/progress reports, research design and methods to assist in the evaluation of the proposals for scientific merit by peer reviewers   • Budget Preparations • Provide the detailed budgets for both the core/base costs and the study proposal funds  • Include personnel efforts and travels for PI and co-PIs to attend 3 SC meetings per year

13. Receipt, Review and Start Dates • Letters of Intent Receipt Date: February 28, 2009 • Application Receipt Date: March 30, 2009 • Peer Review Date(s): June/July 2009 • Council Review Date: October 2009 • Earliest Start Date: December 2009

14. Sending Application to NIH • Submit a signed, typewritten original + checklist + 3 signed copies to: • Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail) Bethesda, MD 20817 (for express/courier service; non-USPS service) • Send 2 copies and all copies of the appendix material to: • Robert Stretch, Ph.D. Director, Division of Scientific ReviewEunice Kennedy Shriver National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01DBethesda, MD 20892Telephone: (301) 496-1485Fax: (301) 402-4104Email: stretchr@mail.nih.gov

15. Review and Selection Process • Evaluated for scientific and technical merit by peer review group • Top half of applications discussed and assigned a priority score • All receive a written critique • Second level of review by NACHHD Council • The following will be considered in making funding decisions • Scientific and technical merit of the proposed project as determined by peer review • Availability of funds • Relevance of the proposed project to program priorities

16. Review Criteria: Qualifications and Commitment of Key Personnel • Scientific, administrative, clinical abilities and academic productivity of the PI, co-investigators and other research team members • Knowledge and experience in areas relevant to collaborative clinical research in pregnancy drug trials (Phases I and II). This should include specific experience in PK and PD analysis and study design and analysis of clinical trials • Commitment of staff time for the satisfactory conduct of the studies

17. Review Criteria: Experience with Protocol and Procedures • Quality of OPRU’s participation in either • (current network members) Network protocols, especially investigator-initiated protocols; or • (new applications) Phase I and II pregnancy drug clinical trials in the recent past • Evidence of successful multidisciplinary research collaborations • Willingness to work and cooperate with other OPRU sites, DCAC and NICHD • Institutional support • Availability of and access to suitable populations as research subjects to participate in OPRU studies • Demonstrated ability to recruit patients for pregnancy drug studies

18. Questions? • Program: Zhaoxia Ren, MD, PhD • (301) 402-9340 • Zren@mail.nih.gov • Grants Management Branch: Bryan Clark • (301) 435-6975 • Brian.Clark@nih.gov • Review: Bob Stretch, PhD • (301) 496-1485 • Stretchr@mail.nih.gov

19. Frequently Asked Questions • Q1.The RFA states that “Applicants may not submit more than one application.”  Does the “applicant” refer to the institution, or to the individual principal investigator?  • A.The “applicants” refer to the individual investigators. An institution may submit more than one application as long as they are scientifically distinct. • Q2. Can we have more than two PIs on the OPRU ? • A. Yes, multiple PDs/PIs are allowed for this RFA. Please refer to NIH guide for details. • Q3. The last RFA included two concept protocols. How many concept protocols can we propose for the new RFA? • A. The applicant should propose at leastone clinical protocol and one basic/translational study protocol within the 20 page limit. • Q4. The new RFA doesn't give much detail about percent/time effort in the budget, what can we include? • A. Given that the multiple PDs/PIs are allowed in this RFA, there will be no maximum/minimum percent/time efforts required for PI or PIs. However, the applicants should indicate a meaningful percent/time efforts to demonstrate his or her commitment in the application.

20. Frequently Asked Questions • Q5.Will there be capitation? • A. Yes, the funds (limited by the direct cost) will be redistributed through DCAC. • Q6. Will there be additional funds for protocol budget cost? • A. No, there will be no additional funds for the protocol costs. The budget $650,000 is the total Direct Cost including the costs for the core facilities and also for the research proposals. • Q7. Will the applications for the RFA be reviewed with NIH new peer-review format? • A. Yes, the NIH Enhanced Peer-Review Criteria will be used for all applications received for this RFA. • Q8. Should I include all five-year budget for both the core/base cost and the concept proposal study costs? • A. Yes, the applicants should provide a five-year detail budget for both the core/base cost, and the concept proposals (clinical and basic/translational studies) costs.

21. Frequently Asked Questions • Q9.If we propose a trial, will the trial be conducted by all members of the OPRU Network? • A. Yes, the PIs who proposed the trials will be the lead for the trials that will be conducted across the network. • Q10. Is the basic science project supposed to be linked thematically to the clinical proposal? • A. Yes, the basic science project and the clinical proposal should be thematically linked, so that clinical materials can be utilized for basic research and the basic science discoveries can be translated into clinical study. • Q11. Is the applicant required to submit one clinical proposal and one basic/translational research proposal for a potential OPRU study?   • A. Yes.  Given the multidisciplinary nature of the OPRU network, the applicant is required to submit at leastone clinical proposal and one basic/translational research proposal within the 20 page limit.