1. Enhancing Clinical and Translational Research at UNMC Lynell Klassen, Jennifer Larsen, Elizabeth Seaquist

2. What is Clinical Research?

3. What Clinical Research is NOT… Research done by an MD Publication of clinical observations Post-marketing observational trials

4. NIH definition of Clinical Research (PHS 398) Patient-oriented research. Research conducted with human subjects (or of human origin - tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, or (d) development of new technologies. Epidemiologic and behavioral studies. Outcomes and health services research.

5. What is Translational Research? There are two types Type 1: Preclinical= bench to bedside –Pre-clinical modeling –Clinically based hypothesis Type 2: Post-clinical= trial to community (best practices)

6. UNMC Clinical Research: Today State-of-the art clinical facilities and specialized regional centers for a variety of diseases with a Children’s Hospital for pediatric specialty care CRC to support investigator-initiated research with space, research nurses, lab, research support Clinical Trials Office for Pharma-driven trials

7. Current Clinical Research enterprise Additional research spaces: Cruzan Center for Dental Research in Lincoln, Clinical research space at OVAMC; but not Children’s Hospital Electronic medical record and nationally known medical informatics expertise Biostatistics/trial design previously in Prev Soc Med moved to the COPH; additional qualitative analysis expertise at UNL Nationally known expertise in human studies regulation and bioethics

8. Current Clinical Research enterprise Growing bioinformatics and biotechnology expertise GMP facility for cellular therapies under construction Expertise in distance learning, web-based data entry, and long distance research collaborations Strong community partnerships with rural communities, minority groups in and outside NE Clinical research training in evolution: Stats-Epi track in MPH, interdisciplinary Clinical Research track within MSIA, and Health Services PhD

9. Building clinical and translational research Elizabeth Seaquist MD Professor of Medicine Program Director, General Clinical Research Center Co-PI, CTSA University of Minnesota

10. BENCHBEDSIDECOMMUNITY

11. A Transforming Approach: NIH Institutional Clinical and Translational Science Awards (CTSA)  Implementing biomedical discoveries made in the last 10 years demands an evolution of clinical science  New prevention strategies and treatments must be developed, tested, and brought into medical practice more rapidly  CTSA awards will lower barriers between disciplines, and encourage creative, innovative approaches to solve complex medical problems  These clinical and translational science awards will catalyze change -- breaking silos, breaking barriers, and breaking conventions

12. How is this transformation achieved? Through the NIH Roadmap for Medical Research, create an integrated environment for the clinical and translational researcher that can provide: –an academic home for clinical research (a Center, Department, or Institute [C/D/I]) –support for protocol preparation, regulatory compliance and data management –support for participant recruitment, human subject safety monitoring –education leading to advanced degrees in clinical research –specialized cores and services for translational research

13. Where are we starting from? Training Programs K12 GCRC Disease X Center Disease Y Center K30 T32

14. NIH CTSA Awards: A Home for Clinical and Translational Science Trial Design Advanced Degree-Granting Degree-GrantingPrograms Participant & Community Involvement RegulatorySupport Biostatistics Clinical Resources Biomedical Informatics ClinicalResearchEthics CTSAHOME Industry Other Institutions

15. NIH Clinical & Translational Science Awards (CTSA)  By 2010 (2012?), all GCRCs and Roadmap training programs (T32/K30/K12) will disappear or be incorporated into a CTSA  Approximately 60 CTSAs will be funded in total  CTSA award will lower barriers between disciplines, and encourage creative, innovative approaches to solve complex medical problems  CTSA award will provide new opportunities for institutions to be truly innovative in proposals to transform their programs and resources to foster clinical and translational science.  Long term goal is to speed discoveries to improved patient care

16. CTSA Specific Objectives (RFA 3/07)  Provide opportunities and resources for original research on novel methods and approaches to translational and clinical science  Provide translational technologies and knowledge base for spectrum of clinical and translational science, including all types and sizes of studies and disciplines  Integrate translational and clinical science by fostering collaboration between departments and schools within institution and between institutions and industry  Provide a point a contact for partnerships with industry, foundations, and community physicians  Provide research education, training and career development leading to a MS or PhD for the next generation of clinical and translational researchers  Conduct self-evaluation activities and participate in a national evaluation of the CTSA program

17. CTSA components 1.Development of Novel Clinical and Translational Methodologies 2.Pilot and Collaborative Translational and Clinical Studies 3.Biomedical Informatics 4.Design, Biostatistics, & Clinical Research Ethics 5.Regulatory Knowledge and Support 6.Participant and Clinical Interactions 7.Community Engagement 8.Translational Technologies and Resources 9.Research Education, Training, and Career Development

18. Organization CTSA resources T32 K30 K12 GCRC Cores Trainee Slots Curriculum Pilot Projects Governance Existing componentsNew CTSA Governance Pilot Projects Curriculum T32 Slots Cores, Clinical Translational Design/Stat/Ethic Community Regulatory Transition existing resources into an integrated program T32 K12 U54 K12 Slots

19. Budgetary constraints I. Only 1 application may be submitted from each degree granting institution Total cost = Combined budgets of existing GCRC/T32/K30/K12 awards + $6 million Institutions like UNMC without GCRC/T32/K30/K12 can request up to $6 million IDC = institutional rate U54 portion, 8% of K12/T32 portion

20. Budgetary constraints II. If more than $4 million total costs above existing GCRC/T32/K30/K12 is requested, applicants must –discuss how they will develop and support translational research and career development in pediatrics –discuss the opportunities that will carry their clinical and translational science endeavors into community settings –describe the institutional commitments that match the increased scale of the program

21. Round one of applications 34 Applications Awards given to 12 centers Columbia University Health Sciences Duke University Mayo Clinic College of Medicine Oregon Health & Science University Rockefeller University University of California, Davis University of California, San Francisco University of Pennsylvania University of Pittsburgh University of Rochester University of Texas Health Science Center at Houston Yale University

22. Round 2 of applications 27 are believed to have applied Up to 8 will be awarded ($38 million available) Review is in May Start date is September 2007

23. Elements of successful applications Strong institutional support ($ ~ equal to grant request + new space, has gone >$100 million over grant period) Clear vision Well integrated Multidisciplinary Innovative

24. How has the University of Minnesota responded to the RFA? Fall 2003: AHC Clinical Research Task Force starts 11/04 Task Force Report released 9/05 AHC Office of Clinical Research opened with Jas Ahluwalia as Executive Director First CTSA RFA released 10/05 10/05-3/06 - Grant planned, written, submitted Application incorporated 36 yr old GCRC with its specialized cores and research support services + newly funded Roadmap K12 + institutional support for industry protocols $66 million in total costs requested Institutional commitment: 30,000 sq ft in renovated bldg for CTSA, renovation of existing 10,000 sq ft GCRC, + ~$50 million over 10 yrs

25. How has the University of Minnesota responded to the RFA? Summer 06: Application not funded (249) Strengths: –Institutional commitment –Training section –Bioethics –Creation of physical home Weaknesses: –organization complexity –lack of details about implementation/integration –all MDs in leadership –unrealistic about potential problems –poor bioinformatics

26. How has the University of Minnesota responded to the RFA? October 06: Second RFA released 10/06-12/06: Draft prepared and rejected - decided to defer to 10/07 3/07: Third RFA released Plan to re-submit October 2007

27. CTSA Review Each application is assigned 8 reviewers and each reviewer is assigned one of following areas 1.Significance, Approach, Innovation, Environment, and Implementation 2.Staffing, Governance, Institutional Commitment, Evaluation Plans 3.Biomedical Informatics 4.Clinical Research Design and Biostatistics,Community Engagement, Regulatory Knowledge and Support 5.Translational Technologies and Resources, Pilot Studies 6.Training 7,8. Overall (Integration, Impact, Anticipates problems)

28. Jasjit S. Ahluwalia, MD, MPH, MS Principal Investigator Translational Jeff Miller, MD (Med) Tim Tracy, PhD (Pharm) Bruce Blazar,MD (Med) Clinical Elizabeth Seaquist, MD (Med) Co-PI CommunityEngagement Mary Story, PhD (SPH) Co-PI Education, Training & Career Development Russell Luepker, MD, MPH (SPH) Co-PI External Advisory Committee Frank Cerra, MD Senior Vice President Academic Health Center Internal Advisory Committee Deans, Mark Paller, Members Eileen Harwood, PhD (SPH) Director, Evaluation Deborah E. Powell, MD Assistant VP Clinical Sciences ICTR Governance

29. CTSA Challenges Balance - Finding balance between describing what you do well and what needs to change is difficult (i.e., Why should NIH give us grant if we already do everything well? vs. If we describe everything that needs changing, it seems negative.) Perspective – All investigators believe what they do is most innovative and deserves highest priority. CTSA includes implicit judgment (e.g., In what order does one list functions? How does the budget get allocated?) Budget - $6 million additional per year is not enough (especially since only $4 million is direct costs) to do all that is asked for in the RFA Change – It is difficult to acknowledge that what we have been doing is not optimal (Clinical Research TF helped) and figuring out how to change it is even more so. Most people will agree to change in the abstract – the devil is in details.

30. CTSA Lessons Learned Be flexible – good ideas can come after initial decisions have been made Listen to the skeptics – they will make your grant stronger Provide a structure for sections early on and don’t let authors argue that the structure “doesn’t fit for my section” Make a timeline that allows time for internal and external review and stick to it It’s never too early to begin gathering biosketches The best sections were drafted early and went through many reviews The best sections incorporated ideas from many individuals Identify reviewers that are not intimately involved with the grant to provide feedback on ideas and to proof read

31. State of clinical and translational research 2013 Clinical and translational research will be supported by a robust network of centers supported by CTSA program Funded centers will collaborate with each other and with unfunded institutions in their region to speed discovery into practice Clinical and translational research will become the preferred career path for talented health professionals

32. What don’t we have? Current clinical research space inadequate-temporary, small, and at Children’s-- nonexistent Clinical research training programs still being developed-clinical research mentor pool still small Clinical research processes are not transparent-no one place, no one person knows everything Processes not efficient: time to contract and time to final IRB approval (benchmark<4-6 weeks), biotechnology licensing, separate IRB approval and credentialing of research personnel at Children’s time consuming

33. What don’t we have? New collaborations slowed by many factors: faculty #, type, or difficult to find No facility to manufacture drugs Mixed messages on value of interdisciplinary clinical research: no space assigned for funded clinical research, only PI given ‘credit’ for research performed by investigator teams Accountability less than clear: who is “in charge” of clinical research?

34. What don’t we have? Serving the larger community –Health data in our hospital, county, or state not easily accessible to evaluate or study health concerns or outcomes –CTSA RFA: need to show how we can move basic research all the way to community implementation and take community concerns back to the laboratory- What will it take to do this?

35. Securing an NIH CTSA A physical and administrative “home” for Clinical research across UNMC Mentored interdisciplinary clinical research training New ways of organizing our research enterprise to speed up translation from bench bedside community: better access to available data, new and innovative ways to gather new data, teams to address health issues, minority and rural community engagement This work can only be accomplished by a team of individuals who have been given institutional authority and committed to UNMC’s success

36. A lot is at stake The final 60 CTSAs will be the driving force behind NIH-funded clinical research for the next 40 years The CTSA is now the model of how clinical research should be done => UNMC needs to transform its research enterprise just to “keep in the game”