JAMA article
looks at data-sharing in Clinical Trials for
Heart Disease
Newswise — How and when
to share clinical trial data for heart
studies -- including when to suspend a study
-- is vitally important to
physician-scientists and regulators as an
increasing number of clinical trials
evaluate new treatments.
This issue is explored
in the April 9 Journal of the American
Medical Association (JAMA) in a commentary
article authored by Dr. Jeffrey S. Borer of
NewYork-Presbyterian Hospital/Weill Cornell
Medical Center and Drs. David J. Gordon and
Nancy L. Geller -- both of the National
Heart, Lung and Blood Institute (NHLBI).
Treatment decisions are
based on findings from scientific studies
called clinical trials that can sometimes
involve many thousands of patients.
Several of these
studies -- such as those involving the drugs
Avandia, Vytorin and, earlier, Vioxx -- have
been the subject of recent controversies in
the media.
Increasingly, clinical trials are monitored
by independent, external groups called Data
and Safety Monitoring Committees (DSMCs),
charged with protecting the safety of trial
participants and preserving trial integrity
and credibility.
These committees are
the only groups that can know results of
blinded trials (trials in which participants
and investigators are not aware of treatment
assignments) while the trials are ongoing.
The proper function of
DSMCs is subject to discussion and debate.
The JAMA article addresses one aspect of
this debate.
"Several situations exist in which it is
reasonable and appropriate for the DSMC to
share interim data from a blinded trial with
operational study personnel and sponsors.
"These
situations might include the need for
'mid-course corrections,' when the number of
outcome events -- like deaths and heart
attacks -- is substantially lower in the
untreated group than was expected in a trial
to reduce such problems," says Dr. Jeffrey
S. Borer, article co-author and director of
Cardiovascular Pathophysiology and
co-director of The Howard Gilman Institute
for Valvular Heart Diseases at NewYork-Presbyterian/Weill
Cornell, and the Gladys and Roland Harriman
Professor of Cardiovascular Medicine at
Weill Cornell Medical College.
"If this happens," Dr. Borer continues, "the
total number of patients slated to
participate in the trial may be inadequate
to test the therapy's effectiveness.
"In
this case, the DSMC might notify the sponsor
and suggest an increase in the number of
subjects to be recruited into the study.
"However,
the DSMC would not tell the sponsor the
number of events that had occurred in each
treatment group."
While sharing some data would be reasonable
and appropriate in several other situations,
Dr. Borer stresses that "the DSMC should
share patient treatment assignments related
to interim outcome/event data with the
sponsor in only one situation -- when
recommending premature termination of the
study."
Reasons the DSMCs recommend termination
include:
* The committee perceives a rising toll of
adverse events that appears to outweigh any
possible benefit from the treatment.
* No evidence of
benefit is apparent, and statistical
analysis suggests that continuation is
highly unlikely to produce such benefit
(called "futility analysis").
* Evidence of benefit
is so overwhelming and important (example:
reduction in death rate) and risks
sufficiently low, that the benefit/risk
relation is highly likely to be maintained
if the trial continued to its planned
conclusion. It would be unethical to
withhold the good treatment, not only from
all trial participants, but also from other
members of society who might benefit.
According to the authors, this decision must
be undertaken with great caution because of
the well-known variability of results over
time, even in large trials.
The article notes that while there are
differences in data-sharing procedures
between industry-sponsored and
government-sponsored trials, all sponsors
"own" their data, and can demand unblinded
information even if this is considered
unwise by the DSMC.
The authors recommend that before doing so,
the sponsor should consider the long-term
consequences of such action, which can
affect regulatory acceptability, future
analyses and publication of the data.
"In such settings, if the DSMC is concerned
that trial credibility or validity will be
compromised by the release of interim data,
there are few avenues open to the committee
except formal protest or resignation," says
Dr. Borer, since no legally constituted
regulatory body has provided relevant
guidance or regulation to deal with the
issue of interim data release.
The authors note that discussion and debate
will continue regarding the appropriate
sharing of interim data as society
increasingly depends on clinical trials for
advancing medical treatments.
The article is based on presentations by the
authors and subsequent discussion held
during the Ninth Cardiovascular Clinical
Trialists (CVCT) Workshop in Paris, France,
in 2006.
The Howard Gilman Institute for Valvular
Heart Diseases at Weill Cornell Medical
College helps cardiologists, cardiothoracic
surgeons and other physicians take advantage
of the most current concepts in the
evaluation and treatment of heart valve
diseases, and provides state-of-the-art
patient care. The Institute's co-directors,
Dr. Jeffrey S. Borer and Dr. O. Wayne Isom,
are leaders in their fields and direct a
team of clinical cardiologists, surgeons and
research scientists who are at the
cutting-edge of this emerging public health
concern. For more information, visit
http://www.gilmanheartvalve.org.
For more information, patients may call
(866) NYP-NEWS .
