1. Vice Chancellor for Clinical Research, Duke University
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. US Clinical trials in crisis
Trial start-up times lengthening
Enrollment slowing
Costs increasing
Many investigators pulling out of clinical research

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

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

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

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

9. Level of Evidence A Current Guidelines*
*Guidelines expressing Level of Evidence AF
Heart failure
PAD
STEMI
Perioperative
Secondary prevention
Stable angina
SV arrhythmias
UA/NSTEMI
Valvular disease
VA/SCD
PCI
CABG
Pacemaker
Radionuclide imaging
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%

10. Level of Evidence C Current Guidelines*
*Guidelines expressing Level of Evidence AF
Heart failure
PAD
STEMI
Perioperative
Secondary prevention
Stable angina
SV arrhythmias
UA/NSTEMI
Valvular disease
VA/SCD
PCI
CABG
Pacemaker
Radionuclide imaging
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%

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. 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. 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. Steering Committee Representation
Category
# organizations
Academic institutions 9
Pharmaceutical companies 8
Clinical research organizations 7
Professional societies 6
Government
6 (FDA [OC,CDER, CBER, CDRH] AHRQ, CMS, NIH, OHRP, VA)
Device companies 5
Biotechnology companies 3
Clinical investigator groups
Trade organizations
Patient representatives/at-large
Private equity firm 1
Regulatory law firm
*Began recruiting members May 2008

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

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. 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. 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. 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 19

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
Describe the range of current monitoring practices and examine factors that drive their adoption
Define key quality objectives for clinical trials
Illustrate strengths and weaknesses of the various monitoring practices in meeting quality objectives for a range of clinical trial settings 20

21. Effective and Efficient Monitoring Project Organization
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
Workstream 2
Project Mgmt

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 22

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)
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
Compare current practice of submitting individual SAEs with an alternative approach based on European Commission’s guidance
Convene an expert group to integrate results and recommend ways to optimize reporting of SAEs to investigators and assure subject protection 23

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. 4th issue Annals of Internal Medicine

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. 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. 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. For more information…. CTTI Website-Home Projects Member organizations
Projects
Member organizations
How to join

29. Clinical Trials 2008; 5: Sensible Guidelines Conference January 25-26, 2007 Sensible guidelines for the conduct of large randomized trials
“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.
What is clear is that such processes are extremely expensive and delay studies.
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.”
Large trials are important
Complexity and cost increasing
GCP ≠ good, or clinically relevant, or even practical
Excess data, number of visits, onsite monitoring
Layers of ethics approvals

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
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
Inclusiveness
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
Califf RM et al, Health Affairs, 2007

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 UK
39.7%
12%
17% 55 US
35.5% 7%
16%
166
Poland
14.8% 2% 9% 2
China
6.1% 5% 1
Argentina
13.6% 8%

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