1. Lysosomal Diseases Network “NIH Funded LDN Investigator Meeting” OFFICE OF RARE DISEASES RESEACH: REPORT (UPDATES/INFORMATIONAL ITEMS) MARCH 4TH, 2016 RASHMI GOPAL-SRIVASTAVA, PH.D. DIRECTOR, EXTRAMURAL RESEARCH PROGRAM (PROGRAM DIRECTOR, RDCRN) OFFICE OF RARE DISEASES RESEARCH (ORDR)

2. Outline Updates Informational Items Reminders Resources and Opportunities at NCATS

3. National Institute of Mental Health National Institute of Neurological Disorders and Stroke National Library of Medicine A View of the National Institutes of Health (NIH), USA National Cancer Institute National Institute on Aging National Heart Lung and Blood Institute National Eye Institute Clinical Center Center for Scientific Review Center for Information Technology National Institute of Environmental Health Sciences National Institute of General Medical Sciences National Institute of Deafness and Other Communication Disorders National Institute of Dental and Craniofacial Research John E. Fogarty Center for Advanced Study in the Health Sciences National Center for Complementary and Alternative Medicine National Center for Minority Health and Health Disparities National Center for Advancing Translational Sciences National Institute of Nursing Research National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of Allergy and Infectious Disease National Institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse National Institute of Biomedical Imaging and Bioengineering National Human Genome Research Institute National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Child Health and Human Development Office of Research on Women’s Health Office of AIDS Research, Office of Dietary Supplements, Office of Behavioral and Social Sciences Research, Office of Disease Prevention, Office of NIH Director Deputy and Associate Directors Administrative Offices Advisory Committee to the Director

4. COUNCIL/ CAN BOARD OFFICE OF THE DIRECTOR EXECUTIVE OFFICE OFFICE OF GRANTS MANAGEMENT & SCIENTIFIC REVIEW OFFICE OF RARE DISEASES RESEARCH OFFICE OF POLICY, COMMUNICATIONS & STRATEGIC ALLIANCES DIVISION OF PRE- CLINICAL INNOVATION DIVISION OF CLINICAL INNOVATION. Petra Kaufman, M.D, M.S, FAAN (Director)

5. Office of Rare Diseases Research (ORDR), NCATS Collaborative Programs/Initiatives Stimulates and coordinates research on rare diseases Rare Diseases Clinical Research Network (RDCRN) Program Rare Diseases Clinical Research Network (RDCRN) Program Genetic and Rare Diseases Information Center (GARD) Scientific Conferences – Identify Research Opportunities and Establish Research Agenda (>1200 Conferences) NIH Clinical Center’s Bench to Bedside Research Program Global Rare Diseases Registry and Repository (GRDR)

7. Goals of the RDCRN Program Facilitate clinical research by:  Creating multi-site Consortia focused on a group of related diseases  Making meaningful large-scale clinical studies possible  Longitudinal studies, Clinical Trials, Natural History Studies are required  Establishing uniform protocols for data collection  Cost sharing infrastructure Collaborate with patients advocacy groups (as research partners), DMCC and NIH scientific staff Train new investigators Support Pilot Projects Program Provide Website resource for education and research in rare diseases Requirements

8. About RDCRN Program Each consortium conducts at least two multi-site clinical studies (including one longitudinal study), has a training program, pilot project program Collectively, the RDCRN is studying 200 rare diseases in natural history and clinical trials at 253 clinical sites located in the US and in 17 countries. There are more than 90 active protocols. 40,000 patients have enrolled in clinical studies. There have been 208 trainees. There are 2,900 collaborative consortium members. There are 138 PAGs as research partners, collectively formed a Coalition (CPAG). http://rarediseasesnetwork.epi.usf.edu/

9. ORDR/NCATS (NCI, NHLBI, NIAID, NIAMS, NICHD, NIDCR, NIDDK, NIMH, NINDS, ODS) The Data Management and Coordinating Center Coalition of Patient Advocacy Groups (CPAG) Dystonia Coalition Brain Vascular Malformation Consortium Nephrotic Syndrome Study Network Porphyria Rare Disease Clinical Research Consortium The Frontotemporal Lobar Degeneration Clinical Research Consortium Primary Immune Deficiency Treatment Consortium Lysosomal Disease Network Autonomic Disorders Consortium Inherited Neuropathies Consortium Rare Kidney Stone Consortium Urea Cycle Disorders Consortium Vasculitis Clinical Research Consortium Chronic Graft Versus Host Disease Rett, MECP2 Duplications and Rett-Related Disorders Consortium Clinical Research in ALS & Related Disorders for Therapeutic Development Sterol and Isoprenoid Diseases Consortium North America Mitochondrial Diseases Consortium Developmental Synaptopathies Associated with TSC, PTEN And SHANK3 Mutations Rare Lung Diseases Consortium Consortium of Eosinophilic Gastrointestinal Disease Researchers Brittle Bone Disorders Consortium Genetic Disorders of Mucociliary Clearance Collaborative Clinical Research Centralized Data Coordination and Technology Development Public Resources and Education Training PAG

10. National Institute of Mental Health National Institute of Neurological Disorders and Stroke National Library of Medicine RDCRN Program: Led by ORDR, NCATS (Collaboration with 10 NIH Institutes--ICs) National Cancer Institute National Institute on Aging National Heart Lung and Blood Institute National Eye Institute Clinical CenterCenter for Scientific Review Center for Information Technology National Institute of Environmental Health Sciences National Institute of General Medical Sciences National Institute of Deafness and Other Communication Disorders National Institute of Dental and Craniofacial Research John E. Fogarty Center for Advanced Study in the Health Sciences National Center for Complementary and Alternative Medicine National Center for Minority Health and Health Disparities National Center for Advancing Translational Sciences, Office of Rare Diseases Research National Institute of Nursing Research National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of Allergy and Infectious Disease National Institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse National Institute of Biomedical Imaging and Bioengineering National Human Genome Research Institute National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Child Health and Human Development Office of Research on Women’s Health Office of AIDS Research, Office of Dietary Supplements, Office of Behavioral and Social Sciences Research, Office of Disease Prevention, Office of NIH Director Deputy and Associate Directors Administrative Offices Advisory Committee to the Director National Cancer Institute National Institute on Aging National Heart Lung and Blood Institute National Eye Institute Clinical CenterCenter for Scientific Review Center for Information Technology

11. RDCRN program: Special Features The RDCRN program is unique in its approach to addressing rare diseases as a group. Each consortium studies a group of minimum three related rare diseases. The direct involvement of PAGs as research partners is a major feature of this network. Collaboration with 10 NIH ICs

12. RDCRN Steering Committee Review, facilitate and establish all Network procedures and functions RDCRCs PIs RDCRN Steering Committee DMCC PI RDCRN-CPAG Chair NIH ICs Project Scientists RDCRN Program Lead & Coordinator (ORDR/NCATS)

13. Upcoming RDCRN-CPAG Meeting May 6 th, 2016 ORDR, NCATS will provide support for one representative per PAG Note: 4 subcommittees of RDCRN Steering Committee - Strategic Planning - Training - Operations - Contact Registry

14. RDCRN Funding **All consortia are co-funded by  ORDR, NCATS and  one or more collaborating NIH Institutes (e.g. Brittle Bone Disease Consortium is funded by NCATS, NIDCR, NIAMS & NICHD)  LDN ** Dystonia consortium award (U54) is funded and managed by ORDR, NCATS. RDCRN-DMCC is funded by ORDR, NCATS

15. RDCRN Program: NIH Institute/Center (IC) Contacts U54 (cooperative agreement award) IC Program Officer (U54 award management and administration, NINDS) IC Project Scientist (Scientific Collaborator, NIDDK) ORDR, NCATS Liaison (attends consortia meetings, participates in site visits etc., is a resource and keeps RDCRN program director from ORDR/NCATS informed) RDCRN Program Director (ORDR/NCATS): Rashmi Gopal-Srivastava, Ph.D.

16. RDCRN Program acknowledgement Publications/presentations must mention in the beginning of the text (when introducing the consortium) or presentation that the consortium is part of RDCRN, an initiative of ORDR, NCATS And In the acknowledgement section: publications/presentations etc. must acknowledge RDCRN support In any presentation (including posters), report, press release or publication resulting from this U54 award, include following points:  “The Name of Consortium (U54XX00000) is part of Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR), NCATS,  This consortium is funded through collaboration between NCATS, and the Name of co-funding NIH Institute(s).”

17. Reminders: Acknowledgement for support from ORDR/NCATS and Others Use the modified RDCRN logo for your consortium related documents (e.g. agenda, flyers, press release etc.) and presentations Please share with all investigators and PAGs in your group and persons involved in submission of manuscript, press release etc. Inform us about the publications, press release

20. Value of PAGs as Research Partners Since 2004 Many PAGs within RDCRN are involved in more than one of the following expanded roles as research partners- Recruit patients for clinical studies, encourage participation in NHS Identify cohorts of patients with range of phenotypic expression Provide financial support for research and training programs of RDCRC (consortia) and patient registries Educate patients, public, media and health care providers Identify research efforts and translate research results to communities Organize and fund research based Scientific conferences and meetings for patients/families/caregivers Provide financial support for travel clinics to facilitate patient access to investigators and studies Establish global partnership

21. New Resources/Initiatives

22. Tissue Chip-RDCRN Program Supplements Purpose: for investigators and institutions currently funded through the NIH Tissue Chip (TC) Program to request supplemental funding that will be used to create and test tissue devices relating to RARE DISEASES utilizing RDCRN program Goal: to create rare disease models that replicate pathology and other in vivo-like responses. The proposed activities must be within the scope of the parent grant. Collaborations with the RDCRN will be a requirement for this supplement. Awards will be issued Summer of 2016.

23. FDA’s Office of Orphan Products Development: Orphan Products Natural History Grants New Program FDA’s OOPD/Office of Special Medical Programs is launching its new Orphan Products Natural History Grants Program To fund targeted rare disease natural history studies to speed the development of new therapies and diagnostics for patients with rare diseases. They plan to commit up to $2 million in the coming year to fund 2 to 5 targeted natural history studies.

24. FDA OOPD’s New NHS Grants Program FDA has developed a video discussion featuring perspectives from patient advocates and agency experts on the importance of rare disease natural history studies and the critical role that patients and patient advocates play in developing this vital information.video discussion To learn more about the new Grants Program, video, visit the OOPD webpage at www.fda.gov/orphan. Look under the Spotlight section. www.fda.gov/orphan

25. California Institute of Regenerative Medicine (CIRM): Funding Opportunity To fund and accelerate the development of stem cell therapies for patients with unmet medical needs. CIRM has almost $1 billion (for stem cell and regenerative medicine) and is looking to invest that in the most promising approaches to combat rare diseases. For researchers and clinicians who are working to move their stem cell therapies for rare diseases out of the laboratory and into clinical trials in people. It is often difficult for projects like this to get the funds needed to complete a clinical trial. Such projects could be eligible to apply to CIRM for funding. For more information: www.cirm.ca.govwww.cirm.ca.gov

26. RDCRN VIP Program Visiting professorship Co-supported by ORDR, NCATS

27. RDCRN Certificate (R25) Program The goal of this Rare Disease Research Training Program is to provide a curriculum and infrastructure for training in rare disease research, and a forum for the networking of new investigators. The main program objectives are the expansion and retention of dedicated investigators in the field of rare disease research by affording new opportunities through the proposed training program.

28. Translational Research Program and Resources at NCATS and other NIH ICs

29. Therapeutics for Rare and Neglected Diseases (TRND) https://ncats.nih.gov/trnd/about Its mission is to encourage and speed the development of new treatments for diseases with high unmet medical needs. TRND stimulates research collaborations among NIH and academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies It provides expertise and resources, working with research partners to move therapeutics through pre- clinical testing, including plans for clinical trials and submission of an IND application to the Food and Drug Administration. These efforts effectively “de-risk” therapeutic candidates and make them more attractive for adoption by outside business partners.

30. Omnibus Solicitation of the SBIR/STTR Grants Application Program NCATS participation, $18M For Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44]) For Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42]) NCATS Contact: Lili M. Portilla, MPA, Portilll@mail.nih.gov, 301-402-0304Portilll@mail.nih.gov 30

31. Selected NIH Translational Research Programs and Resources NCATS – Division of Preclinical Innovation  Therapeutics for Rare and Neglected Diseases Program (TRND)  Bridging Interventional Development Gaps Programs (BriDGs)  Chemical Genomics Center NCATS Division of Clinical Innovation  Clinical and Translational Science Awards (CTSA) Program NICHD  Best Pharmaceuticals for Children Act  Newborn Screening Translational Research Network

32. Selected NIH Translational Research Programs and Resources (Cont.) NINDS NeuroNEXT NHLBI  Centers for Accelerated Innovation  Vascular Interventions/Innovations and Therapeutic Advances  Production Assistance for Cellular Therapeutics  SMARTT (Science Moving towArds Research Translation and Therapy) NCI  NCI Experimental Therapeutics (NExT) Program  Regulatory Assistance Program  Investor Forum

33. Medical Devices

34. Medical Devices for Rare Diseases Needs Assessment Project FDA and ORDR, NCATS joint initiative with multiple stakeholder collaborations  Recommendation in the 2010 IOM Report on Rare Diseases to conduct such an assessment Goal is to highlight the reality that there are important medical device needs for rare diseases which are currently not being met  This effort is not intended to be a comprehensive, granular listing or prioritization of all medical device needs for rare diseases  Web-based survey (2015-2016) 34

35. Orphan Products Grants Program at The Office of Orphan Product Development (OOPD), FDA To promote the clinical development of products for use in the treatment of rare diseases or conditions Annual Budget - $14 million  Clinical trials may be awarded:  Phase I trials – Up to $200K/yr, up to 3 yrs  Phase II & III trials – Up to $400K/yr, up to 4 yrs

36. Precision Medicine Initiative (PMI) http://www.nih.gov/precision-medicine-initiative-cohort-program

37. Learn More About NCATS Questions: info@ncats.nih.gov Like us on Facebook: facebook.com/ncats.nih.gov Follow us on Twitter: twitter.com/ncats_nih_gov Join our listserv, and subscribe to our e- newsletter via links at: www.ncats.nih.gov/news- and-events/e-news/e-news.html ncats.nih.gov

38. Thanks for your attention! Contact: gopalr@mail.nih.govgopalr@mail.nih.gov Rashmi Gopal-Srivastava, Ph.D. Director, Extramural Research Program (Program Director, RDCRN) Office of Rare Diseases Research (ORDR), NCATS

40. THE PRECISION MEDICINE INITIATIVE (PMI) COHORT PROGRAM Thursday, February 25, 2016 : NIH Director joined President Obama at a special White House event to recognize the efforts of federal agencies, companies, and non-profit groups to advance precision medicine. It was just a year ago that President Obama outlined his Precision Medicine Initiative (PMI) to enable a new era of medicine to work together toward development of individualized care. NIH is driving major components of PMI, including the PMI Cohort Program, a landmark longitudinal research study of one million or more U.S. volunteers to expand our understanding of ways we can improve health and treat disease. Our goal is to enroll 79,000 cohort participants by the end of 2016. NIH has taken several actions toward the development of the program, including: -- awarding the Direct Volunteers Pilot Studies Program to Vanderbilt University, Nashville, Tennessee, in collaboration with advisors from Verily (formerly Google Life Sciences), Mountain View, California, to explore the optimal approaches and systems for engaging, enrolling, and retaining participants from across the United States in the PMI Cohort Program. --Volunteers in the pilot will help the research team establish and test innovative methods and technologies for enabling robust participant engagement, as well as user-friendly data collection. This approach will help us learn how to create durable relationships with volunteers, who are partners in the research process, which will be the foundation for a democratized, transformative research environment.

41. THE PRECISION MEDICINE INITIATIVE COHORT PROGRAM -- collaborating with the Health Resources and Services Administration (HRSA) to begin partnerships with several Federally Qualified Health Centers to develop, pilot, and refine approaches for bringing underserved individuals, families, and communities into the PMI Cohort Program, especially those historically underrepresented in biomedical research. -- working with the HHS Office of the National Coordinator for Health IT (ONC) on a program called "Sync for Science," which will pilot use of open, standardized applications to give individuals the ability to contribute their data to research, including for the PMI cohort when it is launched. These pilots will demonstrate a new model of research that enables participants to access their electronic health records, control and manage their data, and coordinate their care among their health care providers, and researchers if they choose. Additionally, the pilot aims to break down silos that too often slow down scientific progress.

42. THE PRECISION MEDICINE INITIATIVE COHORT PROGRAM -- establishing a central PMI Cohort Program Institutional Review Board (IRB)-with expertise in mHealth, bioinformatics, health disparities, epidemiology, genomics, and environmental health -- for oversight and review of the research conducted in the Program. NIH has been at the forefront in creating central IRBs to ensure consistent, thoughtful, and timely review of human research participant issues. All of these actions represent enormous progress in the planning and implementation of this bold initiative. In the coming months, the remaining foundation will be put into place to carry the program's success over the next four to five years and help reach one million participants by the end of 2019. This includes establishing the coordinating center to manage the overall project including the many moving parts and activities that will be required; a network of healthcare provider organizations, which will engage, enroll, and support ambitious data collection for a large segment of the program's participants; a biobank to store and manage biological specimens provided by participants; and a participant technologies center to harness the latest opportunities in mobile phone and sensor technologies in order to assess health outcomes and various influences on health with greater precision than in previous cohort studies.

43.  2. a series of semi-monthly interactive, web-based seminars on methodologies in RDR including study design, statistics, bioethics, therapeutics, policy and approaches to interacting with other key contributors to the field, including patient advocacy groups, federal agencies and biotech/pharma.  3. a semi-monthly “chalk board” videoconference focusing on individual trainee RDR projects with an emphasis on practical design and analytical tools.  4. a web portal with course content, opportunities for interaction among trainees and between trainees and teachers/mentors, and other interactive features

44. 5. a “capstone” research project presentation by each of the trainees at the semi-annual RDCRN meeting that will bring together the trainees, patient advocacy groups, federal agencies and biotech/pharma. 6. Evaluation of program Trainees completing the program will receive a certificate in RDR from the RDCRN.