Steps to Activation of a MultiCenter Clinical Trial

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Steps to Activation of a MultiCenter Clinical
Trial

• Susan B. Shurin, MD
• Deputy Director, NHLBI
• National Institutes of Health

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Process for opening a multicenter trial
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Process for activating a phase III trial with
infrastructure Cancer Therapy Evaluation
Program and Central Institutional Review Board
Dilts, D. M. et al. J Clin Oncol 271761-1766,
2009
http//www.cmrhc.org/process-maps.html for full
process maps
4
Level 0 process flow map for opening an oncology
clinical trial
Dilts, D. M. et al. J Clin Oncol 244545-4552,
2006
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A detail process flow of initial concept
submission illustrating a process loop and a
stopping point
Dilts, D. M. et al. J Clin Oncol 271761-1766,
2009
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Days for each process in opening an oncology
clinical trial in a Cancer Center after protocol
has been received from CTEP
MEAN
MEDIAN
Dilts, D. M. et al. J Clin Oncol 244545-4552,
2006
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Comparison of times for review approval by group

• IRB review and approval median, 47 days
  range, 1 to 426 days
• Scientific Review Committee review and approval
  median, 70 days range, 3 to 566 days
• Contracts and grants review median, 78.5 days
  range, 7 to 461 days

Dilts, D. M. et al. J Clin Oncol 244545-4552,
2006
8
Number of Cancer Therapy Evaluation Program
(CTEP) -sponsored phase III therapeutic oncology
clinical trials activated January 2000 to
December 2007 organized by development time
Dilts, D. M. et al. J Clin Oncol 271761-1766,
2009
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Calendar days for development of a phase III
trial, Cancer Therapy Evaluation Program concept
receipt to activation
Dilts, D. M. et al. J Clin Oncol 271761-1766,
2009
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Why is this so complicated?These are
loosely-coupled systems.
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Loosely-coupled systems

• Individual elements have high autonomy relative
  to the larger system in which they are imbedded.
• Actions in one part of the system can have little
  or no effect on another or can unpredictably
  trigger responses out of proportion to the
  stimulus.
• Linkages among elements are often ill understood
  and/or uneven.
• Forces for are weak compared to the forces for
  specialization.
• Central authority is derived from the members
  rather than the member elements receiving
  delegated authority from above.

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Where does the IRB fit in?
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Protection of Human Subjects

• Effective Unenforceable
• INVESTIGATOR INTEGRITY
• IRB APPROVAL
• INFORMED CONSENT
• Ineffective Enforceable

Enforceable
Ineffective
Courtesy of Eric Kodish M.D.
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IRB Review is Complex
Professional team
Conflicts of Interest
Data sharing
FDA
Publications
HHS
Other govt agencies
DSM
NIH
Accrual
Industry
Adverse Events, UP
Foundations
Hypothesis
Support, oversight
Equipoise
CoI
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Inside an IRB
Leading causes for not approving on first time
through IRB UNKNOWN
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Central versus multiple local IRBs

• Central IRB must be accepted by each local IRB
• CIRB can get strong scientific expertise
• CIRB tends to have well defined processes
• CIRB does not know the local players, may miss
  significant problems with investigators, local
  groups

• Local IRB knows local investigator and
  institutional context better than CIRB.
• Multiple IRB approvals are inefficient,
  duplicative
• Local IRBs are highly qualitatively inconsistent

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How can IRB processes facilitate research more
effectively?

• The IRBs could communicate clear and consistent
  guidelines
• IRBs could ensure that variations in practice are
  coherent, rational and enhance protection
• IRBs could track the reasons for lack of approval
  and help investigators address them

• Investigators can submit proposals which are
  clearly written, follow the guidelines, and are
  in the format requested.
• Networks and cooperative groups can provide
  templates which meet IRB requirements.