1. The Failing Clinical Trial Enterprise in the US: Efforts of CTTI to Improve our National and Global Evidence Generating Capability Robert M Califf MD Vice Chancellor for Clinical Research, Duke University

2. The Official Talk

3. 3 US Clinical trials in crisis  Trial start-up times lengthening  Enrollment slowing  Costs increasing  Many investigators pulling out of clinical research

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5. 5 Clinical Trial Cost Estimates Full Cost Industry Streamlined Industry More Streamlined $ In US 2007 Millions

6. 6 The Globalization of Clinical Investigators Percent of Total 1572s Filed Sources: Tufts CSDD

7. 7 Which Treatment is Best for Whom? High-Quality Evidence is Scarce 7 Tricoci P et al. JAMA 2009;301:831-41

8. ACC/AHA Grading Schema Classification of Recommendations and Level of Evidence Class of Recommendation: value judgment by guidelines authors Class of Recommendation: value judgment by guidelines authors Level of Evidence: objective description of existence/types of supporting studies Level of Evidence: objective description of existence/types of supporting studies

9. Level of Evidence A Current Guidelines* *Guidelines expressing Level of Evidence 11.7% 26.4% 15.3% 13.5% 12.0% 22.9% 6.4% 6.1% 23.6% 0.3% 9.7% 11.0% 19.0% 4.9% 4.8% 0%10%20%30%AF Heart failure PAD STEMI Perioperative Secondary prevention Stable angina SV arrhythmias UA/NSTEMI Valvular disease VA/SCD PCI CABG Pacemaker Radionuclide imaging

10. Level of Evidence C Current Guidelines* *Guidelines expressing Level of Evidence 58.6% 54.3% 25.1% 47.2% 32.0% 8.3% 54.5% 56.5% 29.6% 70.6% 58.5% 47.8% 20.0% 58.2% 26.3% 0%20%40%60%80%AF Heart failure PAD STEMI Perioperative Secondary prevention Stable angina SV arrhythmias UA/NSTEMI Valvular disease VA/SCD PCI CABG Pacemaker Radionuclide imaging

11. 11 It’s a “Systems Problem”  All members of the clinical research enterprise have played a part in this problem  Fixing it will require a collaborative effort  FDA/global regulators  Industry  Academia/NIH  Investigators in clinical practice  Consumers

12. 12 A collaborative effort to find solutions  U.S. FDA’s Office of Critical Path Programs established a public-private partnership: The Clinical Trials Transformation Initiative (CTTI)  All stakeholders involved  Through a memorandum of understanding with FDA, Duke University serves as the host of CTTI

13. 13 Executive Committee Co-Chairs: Rob Califf(Duke) and Rachel Behrman(FDA)  Academia: David DeMets  At-large representative: Ken Getz  FDA: Bob Temple, CDER and Bram Zuckerman, CDRH  Industry: Glenn Gormley, Jay Siegel, Susan Alpert, Alberto Grignolo  Patient representative: Nancy Roach  NIH liaison: Amy Patterson  Non-US regulatory liaison: Hans-Georg Eichler, EMEA  Ex-Officio Members: James Ferguson and Briggs Morrison, Steering Committee Co-chairs; Judith Kramer, Executive Director

14. 14 Steering Committee Representation Category# organizations Academic institutions9 Pharmaceutical companies8 Clinical research organizations7 Professional societies6 Government6 (FDA [OC,CDER, CBER, CDRH] AHRQ, CMS, NIH, OHRP, VA) Device companies5 Biotechnology companies3 Clinical investigator groups3 Trade organizations3 Patient representatives/at-large3 Private equity firm1 Regulatory law firm1 *Began recruiting members May 2008

15. 15 Mission  To identify practices that through broad adoption will increase the quality and efficiency of clinical trials

16. 16 Scope  CTTI will generate evidence about how to improve the design and execution of clinical trials  CTTI will foster widespread change based on evidence  CTTI was created to address a crisis for US clinical research, however…  Trials and issues are global  CTTI seeks to identify practice improvements that can be applied internationally  CTTI is engaging international collaborators

17. 17 Strategy to Accomplish our Mission  Aggressively pursue development of evidence  Conduct “research on research”  Pursue collaborative activities with other organizations sharing similar goals  Parallel activities:  Systematically analyze the clinical trials process and potential impact of our activities  Maintain awareness of other efforts  Promote adoption of CTTI recommendations

18. 18 Initial Priority Areas* for Research on Research  Design principles  Data quality and quantity (including monitoring)  Study start-up  Adverse event reporting *Defined by CTTI’s Executive Committee

19. 19 Status of CTTI Projects  2 Ongoing Projects (with 7 workstreams)  Effective and efficient monitoring as a component of quality assurance in the conduct of clinical trials  Improving the system of reporting and interpreting unexpected serious adverse events (SAEs) to investigators conducting research under an IND  2 Project plans in development  Executive and Steering Committees held a brainstorming session in September  3 Collaborations established

20. 20 Effective and Efficient Monitoring Project  Goal  Identify best practices and provide sensible criteria to help sponsors select the most appropriate monitoring methods for a trial, thereby improving quality while optimizing resources  Specific objectives 1.Describe the range of current monitoring practices and examine factors that drive their adoption 2.Define key quality objectives for clinical trials 3.Illustrate strengths and weaknesses of the various monitoring practices in meeting quality objectives for a range of clinical trial settings

21. 21 Effective and Efficient Monitoring Project Organization Effective and Efficient Monitoring… Rachel Behrman, MD, MPH FDA Co-Team Leader and WS 2 Leader Martin Landray, PhD, MRCP University of Oxford Co-Team Leader and WS 3 Leader Briggs Morrison, MD Pfizer Inc. Co-Team Leader and WS 1 Leader David Nickerson Project Manager Pfizer Inc. Melissa Robb Senior Program Mgr. FDA Workstream 1 Team Workstream 3 Team Workstream 2 Team Project Mgmt

22. 22 Improving SAE Reporting to IND Investigators Goal:  To generate empirical evidence about the current US system for reporting SAEs to investigators under an IND  Consider potential modifications of the current system to more efficiently and effectively inform investigators of these events

23. 23 Improving SAE Reporting to IND Investigators  Subprojects 1.Document current range of sponsor practices for: a. Reporting unexpected SAEs to investigators; b. Oversight of product safety (eg DSMBs, safety committees) 2.a. Quantify investigators’ time spent receiving, interpreting, and communicating individual expedited reports b. Assess perceived value to investigators of individual expedited reports in updating product’s risk profile 3.Compare current practice of submitting individual SAEs with an alternative approach based on European Commission’s guidance 4.Convene an expert group to integrate results and recommend ways to optimize reporting of SAEs to investigators and assure subject protection

24. 24 Collaborations  Use of clinical trials in evaluation of comparative effectiveness  Collaboration between the Center for Medical Technology Policy (CMTP), Pragmatic Approaches to Comparative Effectiveness (PACE), and CTTI  Expert meeting held May 6, 2009—directed to policy- makers —New approaches to clinical trials will make them more attractive for comparative effectiveness research —Manuscript proposing increased operational efficiency, analytical efficiency, and generalizability of clinical trials published in Aug. 4 th issue Annals of Internal Medicine

25. 25 Collaborations (continued)  FDA-initiated training course directed to clinical investigators  Collaborative effort to standardize definitions and data collection methods/case report forms for cardiovascular trials  FDA-initiated effort involving academics, industry, CDISC, and HL7

26. 26 How do we effect widespread change?  Problems with clinical trials widely recognized  Need to go beyond elucidation of problems to effect change  Current behavior often driven by incentives and fears not consistent with the goal of increased efficiency  Decision makers at different levels have variable understanding of the “big picture” —Organizations engage in activities that may not add value —Trade off of cost vs. value not explicit  Wide spread perception that clinical trials just take that long and cost that much!

27. 27 How do we effect widespread change? CTTI’s Approach  Involve all sectors in selection, conduct, and interpretation of projects  Explore the business case for change from different perspectives  Keep dialogue open across sectors  Provide evidence that can influence regulatory guidance  Attempt to create a “level playing field” when recommending change (i.e. don’t place a single organization or sector at risk)

28. 28 For more information….  CTTI Website-Home  www.trialstransformation.org www.trialstransformation.org  Projects  www.trialstransformation.org/projects www.trialstransformation.org/projects  Member organizations  www.trialstransformation.org/members/member-organizations/ www.trialstransformation.org/members/member-organizations/  How to join  www.trialstransformation.org/join

29. Clinical Trials 2008; 5: 38-39 Sensible Guidelines Conference January 25-26, 2007 Sensible guidelines for the conduct of large randomized trials n Large trials are important n Complexity and cost increasing n GCP ≠ good, or clinically relevant, or even practical n Excess data, number of visits, onsite monitoring n Layers of ethics approvals n n “For a scientific method that is at the heart of evidence-based medicine, no good evidence that the layers of complexity, approvals, processes, and laws to protect subjects have actually achieved their purpose. n n What is clear is that such processes are extremely expensive and delay studies. n n Goal: stimulate reform and simplification of clinical trials procedures, while enhancing patient safety and autonomy, improving the scientific validity and integrity of trials and making them more affordable.”

30. Clinical and Translational Science Award (CTSA) At peak a $500 million investment by the NIH in translating scientific discoveries to better human health

31. My Opinion—This does not represent CTTI

32. Disruptive innovation is needed to create a very different system based on electronic data collection in practice with quality built in through a systematic approach.

33. The Cycle of Quality: Generating Evidence to Inform Policy Califf RM et al, Health Affairs, 2007 Measurement and Education Early Translational Steps Clinical Trials Clinical Practice Guidelines Performance Measures Outcomes Discovery Science Data Standards Network Information Empirical Ethics Priorities and Processes InclusivenessInclusiveness Use for Feedback on Priorities Conflict-of-interest Management Evaluation of Speed and Fluency Pay for Performance Transparency to Consumers FDA Critical Path NIH Roadmap 1 2 3 4 5 6 7 8 9 10 11 12

34. The Learning Health System  Articulated goal of the Institute of Medicine  By implementing electronic health records, data warehouses and disease registries, every patient’s data will be used to further knowledge  This means that all places of practice will become research sites  Research must become a normal part of clinical practice, not something done separately from clinical practice (except for very special early phase and highly controlled types of studies)

36. % of Randomized Discontinued in A

37. Protocol Adherence and Adverse Events Non- Adherence Withdrawal: AE’s Withdrawal: Subject preference Withdrew Consent UK39.7%12%17%55 US35.5%7%16%166 Poland14.8%2%9%2 China6.1%5%5%1 Argentina13.6%2%8%1

38. Image Source: http://www.pandora.ca/pictures21/900666.jpg

39. The Demise of Empires  Dominance at a point in time  Arrogance about superiority  Failure to pay attention to quality of work  Leaders content to “ride the wave”  Entrenched interests can buy stability through controlling laws and regulations  Inability to create or respond to innovation  Cost of transactions exceeds cost of actually doing the work!

40. Disruptive Innovation in Clinical Trials  Electronic health records  Data warehouses in integrated health systems  Learning health systems  Use same information for clinical care and research  Electronic permissions systems for participation in research  Evaluation of RESEARCH SITES on a periodic basis with constant electronic surveillance and periodic audits for cause

42. Thank you