Why is Improved Clinical Research Management Important

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
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
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
21 Separate Trials Were Evaluated

• HF ACTION
• IMPROVE IT
• OSIRIS 603
• PAERS
• PPCOS
• REVEAL
• ROCKET
• STITCH
• TACT
• VALGAN
• VX950104

• ACROSS
• ACHIEVE 1
• APPLE
• CABANA
• CAPTN
• COSTAR II
• DILIN PRO
• DILIN RET
• EARLY ACS
• HAP0019

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

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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
ResearchResearch 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 requirementsto guide thenegotiation of
  research contracts.
• JAMA. 20012861232-1234.

Schulman KA, et al. NEJM 20023471335
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Conflict of Interest in Clinical
ResearchResearch Agreements between AMCs and
Industry
Schulman KA, et al. NEJM 20023471335
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Conflict of Interest in Clinical
ResearchResearch Agreements between AMCs and
Industry
Schulman KA, et al. NEJM 20023471335
15
Conflict of Interest in Clinical
ResearchResearch Agreements between AMCs and
Industry
Schulman KA, et al. NEJM 20023471335
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Impugning the Integrity of Medical ScienceThe
Adverse Effects of Industry InfluenceCatherine
D. DeAngelis, MD, MPHPhil B. Fontanarosa, MD,
MBAJAMA, April 16, 2008Vol 299, No. 15
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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

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Agreement
Disagreement
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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
Source
Device firms
Biotech firms
Funding ( in billions)
Pharma firms
Private
State/local
Federalnon-NIH
NIH
1994 1995 1996 1997 1998 1999 2000 2001 2002 2
003
Reproduced from Moses et al., JAMA
20052941333-42
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Cost of Drug Development802 million

• 403M
• out of pocket

• 399M
• capitalization costs

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
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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

24
Sensible Trial Simulation Models

• (1) Full cost pharmaceutical industry
• (2) Streamlined pharmaceutical industry
• (3) More streamlined trial

25
Clinical Trial Cost Estimates
In US 2007 Millions
Full Cost Industry
Streamlined Industry
More Streamlined
26
Delays in Clinical Trial Completion
Sponsor Reported
Site Reported
Percent of Trials Completing

• One-third (35) of trials are substantially
  delayed due to Rescue Mode recruitment
  Activities.
• Ken Getz, CISCRP

Sources ThomsonCenterWatch Veritas Medicine
27
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
28
Cash Flow Challenges
Average Receivable Days for Work Performed
Source CFS
29
PI Turning and Experience
N 5,356
N 3,768
Sources Tufts CSDD
30
Rising Numbers of Complaints Filed Against
Investigators
Annual Complaints Received by FDA
Source FDA Office of Compliance
31
Site Reported Regulatory Burdens

• GCP review at each IM
• Safety Reporting
• Re-consent
• Disclosures
• Source document archiving

Sources Tufts CSDD
32
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

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The Cycle of Quality in Learning Health Systems
Generating Evidence to Inform Policy
Califf RM et al, Health Affairs, 2007
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I skate to where the puck is going to be, not to
where it has been. Wayne Gretzky(the Puck
Stops Here!)