1. RE-ENGINEERING THE CLINICAL RESEARCH ENTERPRISE Working Groups and Co-Chairs Co-Chairs Stephen Katz, NIAMS Stephen E. Straus, NCCAM Subgroups Harmonization of Clinical Research Regulatory Processes Amy Patterson, OSP Integration of Clinical Research Networks, including NECTAR Larry Friedman, NHLBI Stephen Katz, NIAMS Enhance Clinical Research Workforce Training Duane Alexander, NICHD Rob Star, NIDDK Enabling Technologies for Improved Assessment of Clinical Outcomes Deborah Ader, NIAMS Larry Fine, OBSSR Stephen Katz, NIAMS Regional Translational Research Centers Stephen E. Straus, NCCAM Steve Zalcman, NIMH Translational Research Service Cores Josephine Briggs, NIDDK Stephen E. Straus, NCCAM

2. Re-engineering the Clinical Research Enterprise Stephen Katz, M.D., Ph.D Amy Patterson, M.D. Stephen E. Straus, M.D.

3. BenchBedsidePractice Building Blocks and Pathways Molecular Libraries Bioinformatics and Computational Biology Structural Biology Nanomedicine Translational Research Cores Regional Centers Interdisciplinary Research Pioneer Award Public-Private Partnerships Cross cutting: Harmonization, Training Integrated Research Networks Clinical Research Informatics National Clinical Research Associates Patient-reported clinical outcomes Re-engineering Clinical Research

4. Integration of Clinical Research Networks Link existing networks so clinical studies and trials can be conducted more effectively Ensure that patients, physicians and scientists form true Communities of Research

5. Typical NIH Network Academic Health Center Sites & Data Coordinating Center

6. Interoperable Networks Share Sites and Data

7. Integration of Clinical Research Networks Create interoperable Network of Networks National Electronic Clinical Trials/Research Network (NECTAR) Common data standards, informatics Software application tools for Protocol preparation, IRB management, adverse event reports Use existing networks to rapidly address questions beyond their traditional scope BAA-RM-04-23: Feasibility of Integrating and Expanding Clinical Research Networks Inventory and Evaluation of Clinical Research Networks: NIH Task Order 169

8. NIH Career Development Programs College Professional Post-Doc Prof. Advancement Grad School NIH CR Training Program; Trans-NIH K12 CR Career Dev; Advanced Degree Program? National CR Associates Program

9. Trans-NIH Multidisciplinary K12 Career Development Program (RFA) Goal: Promote development of investigators from a variety of disciplines (M.D., Ph.D., R.N.-Ph.D., D.P.H., Pharm.D., D.C., …) To be trained in multidisciplinary team settings Features: Up to 5 years of training Core didactic courses, Project-specific training Mentored research experience in team settings Faculty and mentor support to protect their time Tuition support Annual meetings

10. National Clinical Research Associates Goal: Diverse national group of trained and certified community healthcare providers Will enroll and follow their own patients Accelerate translation of results into practice Steps: Determine feasibility: Barriers? Communities? Incentives needed? Inventory training methods, best practices Develop core competencies, certification Future: Training programs

11. Dynamic Assessment of Patient- Reported Chronic Disease Outcomes Background: Assessment of chronic diseases relies heavily on subjective reports of symptoms and health related quality of life items PROMIS – Patient-Reported Outcomes Measurement Information System: A collaborative network of investigators charged to develop and implement a publicly available system of a large item bank and a Computerized Adaptive Tests for more sensitive and efficient testing of major chronic disease symptoms and functioning. RFA-RM-04-011: Dynamic Assessment of Patient-Reported Chronic Disease Outcomes

12. BenchBedsidePractice Building Blocks and Pathways Molecular Libraries Bioinformatics and Computational Biology Structural Biology Nanomedicine Translational Research Cores Regional Centers Interdisciplinary Research Pioneer Award Public-Private Partnerships Cross cutting: Harmonization, Training Integrated Research Networks Clinical Research Informatics National Clinical Research Associates Patient-reported clinical outcomes Re-engineering Clinical Research

13. Clinical Research Policy Analysis and Coordination Harmonization Initiative

14. Clinical Research: Navigating the Roadway Clinical research impeded by multiple and variable requirements to address fundamentally the same oversight concerns Variability among and within agencies Creates uncertainty about how to comply Hampers efficiency and effectiveness

15. Clinical Research Policy Analysis and Coordination Initiative AIM:Promote clear, effective, and coordinated policies and regulations for the conduct and oversight of clinical research

16. Priority Issues 1. Diverse adverse event reporting requirements 2. Confusion regarding roles and responsibilities of Data Safety and Monitoring Boards, IRBs, and other review mechanisms 3. Variable requirements for auditing and monitoring of clinical trials 4. Absence of uniform standards for electronic submission of safety and clinical research information

17. Priority Issues 5. Confusion regarding applicability of privacy requirements and HIPAA to clinical research 6. Variability in interpretation of the human subjects regulations 7. Central vs. local IRB review 8. Best practices in informed consent 9. Investigator financial disclosure and conflicts of interest

18. Methods Establish formal NIH program to: Work in concert with sibling agencies to catalyze the federal-wide coordination of policies pertaining to clinical research Consult with key stakeholders including IRB, patient, industry, and research communities Develop tools and resources to facilitate understanding of and compliance with clinical research policies and requirements

19. Harmonized Adverse Event Reporting Requirements Gene Therapy Example Prior to January 2002: Principal Investigators had to report to NIH all serious adverse events immediately At variance with FDA requirements (21 CFR 312) Current harmonized requirement: Possibly associated, unexpected events reported within 15 days - or within 7 days if fatal or life threatening Scope, timeframe, and definitions for safety reporting are same for NIH and FDA

20. Analysis and Communication of CR Information Prevailing paradigm Paper based Varied information and diverse formats and vocabularies Inefficient transmission and limited comparison of data sets Model approach Electronic data capture, analysis and reporting Uniform data elements and format accepted by multiple agencies Rapid transmission and ready comparison of data sets Objectives Facilitate investigator compliance Enhance agency oversight Optimize data sharing and analysis

22. Clear, effective, and coordinated rules for clinical research Maximally effective human subjects protections More comprehensive analysis and sharing of research data Enhanced quality and productivity of the research enterprise Outcomes

23. Translational Research Definition: Research at the bench-bedside interface designed to define disease pathobiology and to explore innovative approaches to treatment and prevention A Problem: Academic investigators too often lack the resources and expertise to study diseases or evaluate novel drugs and biologics in early phase (I-II) human studies using state- of-the-art tools

24. BenchBedsidePractice Building Blocks and Pathways Molecular Libraries Bioinformatics and Computational Biology Structural Biology Nanomedicine Translational Research Cores Regional Centers Interdisciplinary Research Pioneer Award Public-Private Partnerships Cross cutting: Harmonization, Training Integrated Research Networks Clinical Research Informatics National Clinical Research Associates Patient-reported clinical outcomes Facilitating Translational Research

25. Translational Research: Goals for the Initiatives Stimulate research at the bench-bedside interface Implement mechanisms to prepare novel products for pre-clinical and clinical studies Ensure adequate support for regulatory oversight, data management, and specimen analyses Increase the sensitivity and impact of early phase clinical studies Invest sufficiently in a modest number of programs to facilitate research at many institutions

26. Translational Research Core Services Extensive consultations with leaders in academia and industry Pilot program will support early pre-clinical development of small molecules for therapeutic applications Modeled on NCI RAID program – Provides investigators access to contractor facilities for key services Requires extensive decision-making expertise, process controls, and regulatory oversight Funded ~25% by Roadmap; ~75% by sponsoring IC Current status: Pilot initiative for implementation in FY2005

27. Regional Translational Research Centers Current options for resources: Regulatory, statistical, bioethics & data management support Support bench-to-bedside and pilot projects, translational research fellows program Cores in some sites for pharmacology, immunology, genetics, microarray, bioinformatics and other highly technical services Could complement NCRRs GCRC program, and support phase I studies of products made by the Core Services program Next Steps: National meeting of academic opinion leaders in summer 2004 Goal is to call for and fund planning grants in FY2005, and rounds of new centers starting in FY2006

28. BenchBedsidePractice Building Blocks and Pathways Molecular Libraries Bioinformatics and Computational Biology Structural Biology Nanomedicine Translational Research Cores Regional Centers Interdisciplinary Research Pioneer Award Public-Private Partnerships Cross cutting: Harmonization, Training Integrated Research Networks Clinical Research Informatics National Clinical Research Associates Patient-reported clinical outcomes Re-engineering Clinical Research

29. Re-engineering Clinical Research: A Work in Progress

30. Re-engineering Clinical Research: Progress To Date (as of February 2004) Multidisciplinary Clinical Research Career Development (K12) programs: RFA-RM-04- 006 Dynamic Assessment of Patient-Reported Chronic Disease Outcomes: RFA-RM-04-011 Inventory and Evaluation of Clinical Research Networks: NIH task order 169 Feasibility of Integrating and Expanding Clinical Research Networks: BAA-RM-04-23

31. Re-engineering Clinical Research: Future 05 Initiatives Translational Research Translational Research Core Services pilot program Planning grants for Regional Translational Research Centers Clinical Research Feasibility of the National Clinical Research Associates program

32. Ideas People Resources Leadership NIH