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Why is Improved Clinical Research Management Important?

Why is Improved Clinical Research Management Important?. Robert M Califf MD Vice Chancellor for Clinical Research Director, Duke Translational Medicine Institute. Clinical Research Management: Key Points.

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Why is Improved Clinical Research Management Important?

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  1. Why is Improved Clinical Research Management Important? Robert M Califf MD Vice Chancellor for Clinical Research Director, Duke Translational Medicine Institute

  2. Clinical Research Management: Key Points • We are entering the era of “learning health systems” in which societal expectations include continuous generation of evidence in the context of practice • The source of this evidence is clinical research • The clinical research enterprise is in serious trouble, especially in the United States • Solutions require a systems approach involving partnerships among practitioners, academia, industry and government

  3. Failings of the System • Too many questions are not answered • Studies are too slow • Studies are too expensive • Investigators are demoralized • This is especially an American problem

  4. 3 2 4 1 DataStandards NIH Roadmap NetworkInformation FDACritical Path Early TranslationalSteps 5 EmpiricalEthics Discovery Science 6 Prioritiesand Processes Measurement andEducation ClinicalTrials Outcomes 12 7 Transparencyto Consumers Inclusiveness 11 8 ClinicalPracticeGuidelines Pay forPerformance PerformanceMeasures Use forFeedbackon Priorities 9 10 Conflict-of-interestManagement Evaluation of Speedand Fluency The Cycle of Quality in Learning Health Systems: Generating Evidence to Inform Policy Califf RM et al, Health Affairs, 2007

  5. ACC/AHA Clinical Practice Guidelines

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

  7. 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 Guidelines: More GuidelinesNo Improvement in Proportion with High Quality!

  8. Major Milestones –Operational Metrics LastPatientClean Final Protocol LastPatient Study Materials Sent ProtocolSent FirstPatient LastVisit Lock/RevealData

  9. ACROSS ACHIEVE 1 APPLE CABANA CAPTN COSTAR II DILIN PRO DILIN RET EARLY ACS HAP0019 HF ACTION IMPROVE IT OSIRIS 603 PAERS PPCOS REVEAL ROCKET STITCH TACT VALGAN VX950104 21 Separate Trials Were Evaluated

  10. Time for IRB Review and Contract Execution • Time from IRB submission to approval • Average: 136 days • Range: 17-360 days • Time for contract execution • Average: 137 days • Range: 7-272 days

  11. Despite all of the administrative work we are not seeing improvement in study start up times in the US!

  12. Conflict of Interest in Clinical Research:Research Agreements between AMCs and Industry Do research agreements between medical schools and industry sponsors adhere to the standards embodied in the new ICMJE guidelines? “We encourage investigators to use therevised ICMJE requirements…to guide thenegotiation of research contracts.” JAMA. 2001;286:1232-1234. —Schulman KA, et al. NEJM 2002;347:1335

  13. Conflict of Interest in Clinical Research:Research Agreements between AMCs and Industry —Schulman KA, et al. NEJM 2002;347:1335

  14. Conflict of Interest in Clinical Research:Research Agreements between AMCs and Industry —Schulman KA, et al. NEJM 2002;347:1335

  15. Conflict of Interest in Clinical Research:Research Agreements between AMCs and Industry —Schulman KA, et al. NEJM 2002;347:1335

  16. Impugning the Integrity of Medical ScienceThe Adverse Effects of Industry InfluenceCatherine D. DeAngelis, MD, MPHPhil B. Fontanarosa, MD, MBAJAMA, April 16, 2008—Vol 299, No. 15

  17. Consistency of Conflict of Interest Reporting • Searched PubMed for English-language articles published in 2006 that provided evidence or guidance regarding the use of coronary artery stents • Resulting database of 746 articles, 2985 authors, and 135 journals • Recorded article characteristics, including information about authors’ financial disclosures • Main outcome measures were the prevalence, nature, and consistency of financial disclosures • Weinfurt KP; PLOS 1, May 7th, 2008

  18. Agreement Disagreement

  19. Interpretation • In rare instances when financial interests were disclosed, they were not disclosed consistently, suggesting problems with transparency in the literature • An inconsistent system of disclosure may be more harmful than no disclosure at all, because it creates the impression rather than the reality of transparency • The relative contributions of journals and authors to this problem are unclear

  20. 100 – 80 – 60 – 40 – 20 – 0 – Source: Device firms Biotech firms Funding ($ in billions) Pharma firms 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

  21. $399M capitalization costs* $403M out of pocket Cost of Drug Development:$802 million *Assumes discount rate of 11% to time of market approval. $282M clinical costs $121M pre-clinical costs DeMasi, Hansen and Grabowski, Jl of Health Economics 2003 …and increasing

  22. Expert Panel Recommendation Areas: (1) Increase ability of sites to become top performers • -Manage increasing workload • -Competition for patients • -Increase performance (2) Use computers to improve site management and monitoring (3) Streamline and enhance clinical trial operations

  23. Sensible Trial Simulation Models (1) Full cost pharmaceutical industry (2) Streamlined pharmaceutical industry (3) More streamlined trial

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

  25. Delays in Clinical Trial Completion One-third (35%) of trials are substantially delayed due to ‘Rescue Mode’ recruitment Activities. Ken Getz, CISCRP Site Reported Sponsor Reported Percent of Trials Completing… Sources: ThomsonCenterWatch; Veritas Medicine

  26. Investigative Site Operating Profit(With and Without Hidden Cost Adjustments) Source: CenterWatch and Rapidtrials, July 2003. Assumes total average hidden costs per trial of $7,753

  27. Cash Flow Challenges Average Receivable Days for Work Performed Source: CFS

  28. PI Turning and Experience N = 5,356 N = 3,768 Sources: Tufts CSDD

  29. Rising Numbers of Complaints Filed Against Investigators Annual Complaints Received by FDA Source: FDA Office of Compliance

  30. Site Reported Regulatory Burdens • GCP review at each IM • Safety Reporting • Re-consent • Disclosures • Source document archiving Sources: Tufts CSDD

  31. Takeaways • Critical need to optimize sponsor-site collaborative effectiveness • Highly volatile investigative site landscape • Largely private-sector, community-based • Increasingly global • Facing difficult operating challenges • High turnover and rising levels of non-compliance • Leverage Areas: • Site identification and selection • Contracting and budgeting • Site management • Regulatory • Site training and education

  32. 3 2 4 1 DataStandards NIH Roadmap NetworkInformation FDACritical Path Early TranslationalSteps 5 EmpiricalEthics Discovery Science 6 Prioritiesand Processes Measurement andEducation ClinicalTrials Outcomes 12 7 Transparencyto Consumers Inclusiveness 11 8 ClinicalPracticeGuidelines Pay forPerformance PerformanceMeasures Use forFeedbackon Priorities 9 10 Conflict-of-interestManagement Evaluation of Speedand Fluency The Cycle of Quality in Learning Health Systems: Generating Evidence to Inform Policy Califf RM et al, Health Affairs, 2007

  33. “I skate to where the puck is going to be, not to where it has been.” Wayne Gretzky(the Puck Stops Here!)

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