Hanging Together or Hanging Separately: the Imperative for Consortium Action

1. Hanging Together or Hanging Separately: the Imperative for Consortium Action Robert M Califf MD Vice Chancellor for Clinical Research

2. “We must all hang together or most assuredly we will all hang separately.” Benjamin Franklin quotes (AmericanStatesman, Scientist, Philosopher, Printer, Writer and Inventor. 1706-1790)

3. Key Points • Society is expecting a rapid expansion of evidence development by our clinical research enterprise • Development of new technologies (diagnostics, drugs, devices, behavioral interventions) • Comparative effectiveness is seen as a lynchpin of health care reform by providing rational basis for choices in use of technologies • Academic medical centers provide the fundamental education of clinical research professionals—this is when key professional habits and expectations are formed • AMCs have become Academic Health Systems—distributed systems account for large segment of “community practice” in the US • Clinical research is a significant part of the American economy

4. Key Points • As AMCs we are not delivering the goods • We should not confuse “academic” with “inefficient” • Clinical research should answer important questions with sound design—almost all good researchers want to be freed from non-value added administration so they can focus on their research • The operations of clinical research resemble other systems that combine human effort and technology to produce a product—standardization and systems development and measurement can produce a better product • Patient advocacy groups consistently identify these delay times as adverse to the interests of patients

5. By standardizing systems and providing transparency we can free our researchers to do the research that is a critical societal need. By definition, standardization takes a consortium!

6. Academic Of theoretical interest, but no practical importance

7. Investmentin Biomedical Research Source: Device firms 100 – 80 – 60 – 40 – 20 – 0 – Biotech firms Pharma firms Funding($ in billions) Private State/local Federal—non-NIH NIH 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 Reproduced from Moses et al., JAMA 2005;294:1333-42

8. Declining Productivity Number of NDAs • Global R&D spending growth 6% annually between 1997 and 2008 • Rolling 3-year average of NDA Approvals declining steadily over past 15 years Source: FDA, IMS International

9. Life Expectancy Around the World

10. The United States spends far more on health care than expected even when adjusting for relative wealth Per capita health care spending, 2006$ at PPP* 2006 R2=0.88 United States Spending above ESAW** Switzerland Austria France Iceland Canada Germany Denmark Portugal Spain Finland South Korea Poland CzechRepublic Per capita GDP $ * Purchasing power parity. ** Estimated Spending According to Wealth. Source: Organisation for Economic Co-operation and Development (OECD)

11. ACC/AHA Clinical Practice Guidelines

12. ACC/AHA Guidelines: Level of Evidence of Recommendations LoE A LoE B LoE C

13. A B C A B C A B C A B C A B C A B C Atrial Fibrillation (2001-2006) Heart Failure (2001-2006) Stable Angina (1999-2002) Unstable Angina (2000-2007) PCI (2001-2005) Pacemaker (1998-2002) ACC/AHA CV GuidelinesNo Improvement in Proportion with High Quality!Tricoci et al.JAMA.2009; 301: 831-841

14. BMJ 2003

15. Data gathered by the Tufts Center for the Study of Drug Development (Tufts CSDD) • >90% of all clinical trials delayed due to over-ambitious timelines and difficulty with patient enrollment • Top reasons for delays in trials: • Protracted budget negotiations • Slow IRB review and approval • Poor patient recruitment and retention • Estimated 20% of PIs fail to enroll a single patient and 30% under-enroll in a given trial • Between 2000 and 2005 38% of PIs who participated in clinical trials in a given year did not return in a subsequent year through 2008 • Up from 26% in previous 5 years

16. Conclusion: Too many non-value added (NVA) steps Moving of paper back & forth Batching clinical trials (builds an inventory) Excess processing (how many tracking numbers track a study?) Waiting for something to be done Corrections / Pre-Opening Amendments Motion (making multiple copies instead of electronic transmission) Overproduction (i.e., doing what doesn’t need to be done) Value-Added steps are those that: Impact the quality, safety or effectiveness of the study Note: if a study does not achieve its minimum accrual goal, then all steps are NVA

17. Final Accrual Performance* of CTEP-Sponsored Phase III Trials Opened and Closed between 2000 – 2007 (n=61) 36.1% meet or exceed minimum projected accruals 63.9% do not achieve minimum projected accruals at closure - 5,776 patients accrued to these studies 49.2% do not achieve 25% of minimum projected accruals at closure • Accrual Performance is calculated based on the percentage of final accruals of studies completely closed to accrual compared to the projected minimum accrual goals as stated at the time of activation • Pediatric studies are excluded from the sample

18. Patient Recruitment and Retention • Performance data on 57 phase II and III (across TAs) protocols provided by five pharmaceutical companies Source: Tufts CSDD

19. ECOG Phase III Accrual Performance • All phase III studies activated and closed to accrual between 1/2000 – 7/2006 • Color Code: • red : studies taking greater than the median time to open • blue: studies taking less than the median time to open • gray: studies closed due to reasons other than poor accrual

20. Impact of Development Time on Accrual Success of CTEP Trials Cheng, S “The Impact of Delay” Vanderbilt PhD Dissertation, 11/2008 n=40 n=109 n=127 n=104 n=55 n=47 n=21 n=15 n=35 • Odds Ratios calculated using binary logistic regression adjusting for study size • Dotted line indicates the referent as defined as the median development time of the sample • Squares represent the odds ratio; vertical lines represent 95% CI

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

22. 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!

23. Why Change? Remember When (1970’s) 1970 Corvette Stingray 1970 Toyota Carina

24. 1998 - Chrysler sold to Daimler for $30.5 billion 2007 - Sold to Cerberus for ~$1b (actually they paid Cerberus to buy Chrysler if pension liabilities retained by Daimler are taken into account) 2009 -Sold yesterday to Fiat for $0 upfront cash (who, in 2005, got $2b when GM backed out of the deal to buy them)

25. But we’re not a car company!

26. Since 2002, the number of FDA investigators outside the US has grown by 15% annually, while the number inside the US has declined by 5.5%. • One-third of phase 3 trials of the 20 largest US pharmaceutical companies are being conducted solely outside the US. • For those same firms and studies, a majority of study sites (13,521 of 24,206) are outside the US. Source: Glickman, SW et al. NEJM 2009

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

28. Cycle Time Metrics 69% - 75% Increase 12% – 20% Increase Median Days Elapsed Source: Tufts CSDD

29. Protocol Designs More Complex and Burdensome (2000-2006) Annual Growth Rate Compensation per Procedure Represents 10,038 industry protocols; provided by Fast Track Systems Work effort values based on Medicare’s RVU methodology Sources: Tufts CSDD; Getz et al. Assessing the Impact of Protocol Design Change on Clinical Trial Performance. American Journal of Therapeutics. 2008 15(5); 450 - 457

30. Ongoing Dialogue Regarding Operational Efficiency of NCI Clinical Trials • “Cooperation with CTSA program may create synergies and address common concerns” • “From discussions with Cancer Centers conducted under the aegis of the Cancer Center Prioritization subcommittee, it appears the CTSA programs at many Cancer Centers may not be sufficiently well-established so that increased collaboration would be useful at this time. Should inclusion of this recommendation therefore be reconsidered?”

31. Whose fault is it ?The Good News—We are all sinners! • Investigators (33%) • Institutions (33%) • Sponsors (33%)

32. Learning from Health Care Quality Efforts • Use evidence • Implement proven measures in a reliable and efficient manner • Measure, measure, measure • It’s a team effort • Reward success—work with those who fail

33. Summary of Hospital Compare AMI Measures (2005 data)

34. Threshold for “Top Hospital” Status in 2005

35. McDonalds vs the US Healthcare Profession? Provider Napkin and Ketchup in Bag Quality Metric Beta-blocker Or anti-platelet therapy <50% at many locations >99% given At any location Performance

36. A collaborative effort to find solutions In light of these issues the U.S. FDA’s Office of Critical Path Programs and Duke University joined together as founding members of a public-private partnership: The Clinical Trials Transformation Initiative (CTTI) All stakeholders are involved in this initiative including government, industry, academia, patient advocates, clinical investigators, professional societies, and others

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

38. Member Organizations *Began recruiting members May 2008

39. Projects Priority areas defined by Executive Committee: Design principles Data quality and quantity (including monitoring) Study start-up Adverse event reporting Information about the process for submission, review, and approval of projects available at CTTI Web site: www.trialstransformation.org/projects

40. The Need for Standards:the National Bureau of Standards “The need for standards was dramatized in 1904, when more than 1,500 buildings burned down in Baltimore, MD, because of a lack of standard fire-hose couplings. When firefighters from Washington and as far away as New York arrived to help douse the fire, few of their hoses fit the hydrants. NIST had collected more than 600 sizes and variations in fire-hose couplings in a previous investigation...

41. Standardization • What if 39 to 60 AMCs and the NIH agreed on anything? • What if FDA, academia and industry agreed on anything? • Likely de facto standards!

42. What can the CTSA Consortium do? • Agree on a standard set of metrics for study startup • Make them public after a “run in” period • Agree on a standard set of contracting terms, at least for multicenter clinical trials and epidemiological studies • Continue very active IRB sharing work • Best practices of IRB • Training investigators so IRBs don’t waste their time

43. Future/Concurrent Issues • Research subject/patient recruitment • Simplification by using electronic health records/disease registries • Identifying non-value added steps related to Federal regulations, and eliminating them • Each institution solving its local problems but sharing them in a way that creates generalizable solutions