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WHY SOME CLINICAL TRIALS DO NOT WORK OR HAVE AN IMPACT. ARE THERE WAYS TO DO A BETTER JOB? An International Society of Cardiovascular Pharmacology (ISCP)-CVCT joint session

Chairpersons: Angeles Alonso (London, GBR), Milton Packer (Dallas, USA)
2.00 pm – 6.30 pm
 The structure of a large international clinical trial is complex. It typically involves a
sponsor, a leadership committee, numerous geographically-dispersed
investigators, and a group responsible for operational functions.
 A pharmaceutical executive or academic leader must decide whether to propose
a very large expensive clinical trial to upper management. The data supporting
the drug is marginal. He/she advocate strongly for investment, emphasizing data
that are hopeful but minimizing risks.
 The leadership committee defines the trial hypotheses and the methods by which
the hypotheses can be tested in an unbiased manner. Members focus on the big
picture, but do they really know how the trial is being executed?
 Most sponsors lack internal resources to execute the trial and thus seek help from
an outside vendor, a CRO. Their procurement office provides the contract to the
lowest bidder.
 The CRO is itself a business enterprise, which has a responsibility to carry out the
trial in a manner financially advantageous to its owners or shareholders. They
identify investigators who can recruit quickly and inexpensively.
 The investigators are paid to recruit patients. Some are very creative in enrolling
patients very quickly. When the trial is over, they will receive little academic credit,
but will rapidly move on to the next trial.
 The operations group is charged with ensuring that patients are recruited into the
trial on schedule and that the data quality can be made to appear to be
reasonable.
 The data are collected, but the analysis unit understands that certain results will
yield predictable benefits. If this is a phase II trial, a trial yielding positive results
is likely to be followed by additional substantial investment in more studies.
 If this is a phase III trial, the results are rarely satisfying; i.e., the trial’s primary
hypothesis has proven to be valid, and the supporting data are of very high
quality. Much more often than not, both the leadership committee and the
sponsor are disappointed by the results. There may be some positive signals, but
one can find them only after a very diligent and creative search.
 The results of the trial are presented, and internet scavengers emerge from their
hiding places to feast. If the trial is markedly positive, these vultures seek
perceived flaws or hold the trial’s conduct to unrealistic standards. If not, they
demand replication (even if it is unethical or not feasible). If the results are
disappointing, they rejoice in their claims that they predicted the trial’s failure.
 The results of the trial are published. How should a new study be interpreted?
Many physicians do not even make an attempt to read and understand the
primary publication; often they wait for the chatter on the internet or official
guidelines to tell them what to do. Physicians have insufficient knowledge, time or
motivation to perform a proper evaluation.

An overview of the problem seen from the US
Milton Packer (Dallas, USA)
How do sponsors make a decision to support a trial?
David Kallend (The Medicine Company, USA)
Kenneth Stein (Boston Scientific, USA)
Can academic leaders oversell an idea?
Paul Armstrong (Edmonton, CAN)
Karl Swedberg (Gotheborg, SWE)
Who should be minding the store?
Janet Wittes (Statistics Collaborative, USA)
Why do I sometimes have trouble sleeping at night?
Scott Solomon (Boston, USA)
Are academic investigator becoming extinct?
Bertram Pitt (Ann Arbor, USA)
Which types of investigative sites do regulators worry about?
Norman Stockbridge (FDA, USA)
Are practitioners paying any attention to the results of trials?
Antoni Martínez-Rubio (Barcelona, ESP)
What do journal editors think of professional cynics?
Stuart Spencer (The Lancet, GBR)
John Jarcho (NEJM, USA)
Joe Hill (Circulation, USA)
Robert M. Golub (Jama, USA)
Are payers happy when a trial shows a benefit of an expensive drug?
Leeza Osipenko (NICE, GBR)
Media Viewpoint: Ron Winslow (Wall Street Journal, USA)

THE FORUM
Moderated discussion with the audience
Chairpersons : Angeles Alonso (London, GBR), Milton Packer (Dallas, USA)
Panelists: Angeles Alonso (London, GBR), Paul Armstrong (Edmonton, CAN), Robert M.
Golub (Jama, USA), Joe Hill (Circulation, USA), Larry Husten (CardioBrief, USA), John
Jarcho (NEJM, USA), David Kallend (The Medicine Company, USA), Antoni Martínez-
Rubio (Barcelona, ESP), Leeza Osipenko (NICE, GBR), Milton Packer (Dallas, USA),
Bertram Pitt (Ann Arbor, USA), Scott Solomon (Boston, USA), Stuart Spencer (The
Lancet, GBR), Kenneth Stein (Boston Scientific, USA), Norman Stockbridge (FDA,
USA), Karl Swedberg (Gotheborg, SWE), Ron Winslow (Wall Street Journal, USA),
Janet Wittes (Statistics Collaborative, USA)