Transcript Coaated stents: a new era

CONVINCE
CONVINCE: The ethics of stopping
a clinical trial
Eric J Topol MD
Provost and Chief Academic Officer
Chairman, Department of Cardiovascular Medicine
The Cleveland Clinic Foundation
Cleveland, OH
Robert M Califf MD
Professor of Medicine
Associate Vice Chancellor for Clinical Research
Director, Duke Clinical Research Institute
Duke University Medical Center
Durham, NC
Thumbs up/Thumbs down – May 2003
CONVINCE
CONVINCE: Trial design
Controlled Onset Verapamil Investigation
of Cardiovascular End Points
• 661 centers in 15 countries, 16 602
hypertension patients with at least 1
additional CVD risk factor
• Randomized to controlled-onset
extended-release (COER) verapamil or
standard therapy (initial atenolol or
hydrochlorothiazide)
• Primary end point: fatal and nonfatal MI,
fatal and nonfatal stroke, and death from
cardiovascular disease
Thumbs up/Thumbs down – May 2003
CONVINCE
Reasons for stopping the trial
Pharmacia chose to stop the trial,
citing "business reasons"
Societal responsibilities of clinical trial
sponsors. Lack of commercial pay-off
is not a legitimate reason for
stopping a trial
Evans S, Pocock S. BMJ 2001; 322: 569-70
A "tremendous effort" was made by
the investigators to gather all the
data and present it
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Califf
CONVINCE
CONVINCE: Blood pressure
Verapamil
Atenolol or hydrochlorothiazide
14
BP reduction
(mm Hg)
12
10
8
6
4
2
0
Systolic
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Diastolic
Black HR et al. JAMA 2003;289:2073-82
CONVINCE
CONVINCE: CV events
Event
Hazard ratio*
95% CI
p
Primary CVD
events
1.02
0.88-1.18
0.77
Stroke
(fatal or nonfatal)
1.15
0.90-1.48
0.26
MI
(fatal or nonfatal)
0.82
0.65-1.03
0.09
CVD mortality
1.09
0.87-1.37
0.47
All-cause mortality
1.08
0.93-1.26
0.32
*verapamil vs atenolol or hydrochlorothiazide
Black HR et al. JAMA 2003;289:2073-82.
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CONVINCE
Falling short
Unable to show superiority of
verapamil for events between 6 AM
and noon
Unable to declare superiority or
noninferiority due to lack of
statistical power
• Prespecified boundary for
noninferiority: HR=1.16
• Upper bound for primary events:
HR=1.18
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Califf
CONVINCE
CONVINCE: Adverse events
Events (%)
Verapamil
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Atenolol or hydrochlorothiazide
Death or
hospitalization for
bleeding
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New cancer
Black HR et al. JAMA 2003;289:2073-82
CONVINCE
First drug
Thiazide diuretic remains the standard
drug to start with for hypertension
patients
Race doesn't seem to modify the
advantage of starting on a thiazide
but does influence the choice of
using an ACE inhibitor in addition
Topol
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CONVINCE
First drug
Everyone should be started on a
thiazide unless there is some
specific countervailing issue
• (ie) Post-MI patient with mild
hypertension who should be on a
beta blocker
ACE-inhibitor is the next line of
therapy in many people
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Califf
CONVINCE
A new precedent
This decision sets a new precedent. It
was a pathetic decision
Stopping medical research to save
money: a broken pact with
researchers and patients.
Psaty BM, Rennie D. JAMA 2003; 289:2128-31
"It was unthinkable to me that a
large-scale trial could be
stopped by industry because of
purely business reasons."
Thumbs up/Thumbs down – May 2003
Topol
CONVINCE
Crimes of clinical research
Patients were taken advantage of
"I don't know that it crosses the line
of crimes against humanity, but
it's definitely crimes of clinical
research."
Patients volunteer and end up
suffering possible adverse events
for no meaningful data
"The whole thing is a disaster."
Topol
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CONVINCE
Why was the trial done?
How many people already get
verapamil as a sole drug?
The primary point was to show
noninferiority
Major subgroup was to look at earlymorning events
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CONVINCE
Better care
Blood-pressure reductions seen in the
trial were better than general
practice in all arms
Patients got better than usual care
and were monitored over time
Nothing experimental or invasive
about the treatment
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Califf
CONVINCE
Prioritizing research
A company has a portfolio of research
to do and choices must be made
because a profit must be made
"If this trial had been continued
there would have been products
that would not be developed . . .
because it would have taken
money that would have gone to
develop new things, one of which
was eplerenone."
Thumbs up/Thumbs down – May 2003
Califf
CONVINCE
Respecting human research
These decisions of priorities must be
made when a trial is started
• Once started, a trial must be
allowed to go to its natural
completion
• Companies have multiyear
planning and can't suddenly
change their minds
"That whimsical nature is not
allowed. It's unethical and
unacceptable."
Thumbs up/Thumbs down – May 2003
Topol
CONVINCE
Financial woes
Bankruptcy might be a legitimate
reason to stop a trial
Bankruptcy in the middle of a large,
multicenter trial would catch
researchers by surprise
"Anytime you're going into a
megatrial . . . that assumes the
resources are there to complete
the experiment."
Topol
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CONVINCE
"Whatever it takes"
Centecor ran out of money in
midstream on its sepsis drug
"We floated them to get the darn
thing done because we would
never have accepted stopping a
trial or stopping a follow-up.
That would be untenable."
"Whatever it takes, they've gone
this far, they've got to get the
thing done."
Topol
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CONVINCE
Tightening the ship
It is possible the pending sale of
Pharmacia to Pfizer influenced the
decision
• "Tightening the ship" to make the
company a more attractive
purchase
It never has been stated exactly what
the business case was
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Califf
CONVINCE
Hospital priorities
There is always a problem factoring
human ethical concerns into the
medical business
How different is this from a hospital
pushing patients to the most
profitable DRG categories?
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Califf
CONVINCE
Ethics of research
Clinical research is a bilateral consent
of patients and investigators
"The ethical standards of research,
and selling out human beings for
business purposes, we can't let
that ride."
"Industry needs to take notice that
we're not going to put up with
this kind of thing."
"There should never be another
CONVINCE misadventure in the
future."
Thumbs up/Thumbs down – May 2003
Topol
CONVINCE
A human on the balance sheet
Happy to lose this argument
"I'm afraid that in today's society,
many components of the medical
products business and even the
hospital industry lose sight of
the fact that there's a human
being at the other end of the
balance sheet."
Thumbs up/Thumbs down – May 2003
Califf
CONVINCE
Bivalirudin
Bivalirudin trials were stopped for
business reasons
Dr Eugene Braunwald was not
consulted, just called into an
investigators’ meeting and told the
trial would be stopped
In retrospect, bivalirudin has been
shown to be an interesting drug
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CONVINCE
Exploitation
The same message to industry being
sent now should have been sent
then
"Once a decision's been made to go
forward with a trial, that's a pact
that has to go to a natural
completion. Otherwise it is
exploiting human beings, which
we don't want to be party to."
Topol
Thumbs up/Thumbs down – May 2003
CONVINCE
Thumbs
Califf: "Two thumbs down to the trial
and two thumbs up to the steering
committee, who heroically persisted
in getting the data."
• Two thumbs down
Topol: "I completely agree with you."
• Two thumbs down
Thumbs up/Thumbs down – May 2003
CONVINCE
CONVINCE: The ethics of stopping
a clinical trial
Eric J Topol MD
Provost and Chief Academic Officer
Chairman, Department of Cardiovascular Medicine
The Cleveland Clinic Foundation
Cleveland, OH
Robert M Califf MD
Professor of Medicine
Associate Vice Chancellor for Clinical Research
Director, Duke Clinical Research Institute
Duke University Medical Center
Durham, NC
Thumbs up/Thumbs down – May 2003