Download 030403 Controlling Research Trials

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Controlling Research Trials
Jeffrey M. Drazen, M.D.
Clinical research, especially in the form of large
multicenter trials, promotes changes in practice;
without the accrual of new knowledge, clinical care
will not advance. A deadlock between the National
Heart, Lung, and Blood Institute (NHLBI) and the
Office of Human Research Protections (OHRP) of
the Department of Health and Human Services
about the ethics of a clinical trial has the potential
to bring much clinical research to a halt. The trial in
question is designed to examine the ability of intravenous-fluid management directed by physiological data obtained from a pulmonary-artery catheter
to influence outcomes in medical intensive care
units. At the request of the OHRP, this trial has been
on clinical hold since July 2002.
To have a clear sense of the issues at play, it is
important to understand the process by which trials sponsored by the National Institutes of Health
(NIH) are designed and implemented (Fig. 1). When
members of the medical community note a clinical
problem that is in need of better research data, they
bring it to the attention of appropriate members of
the NIH staff. If the problem appears to be important, the staff members draft a request for research
proposals and submit it for evaluation by the advisory council of the sponsoring institute. At this stage,
there are often many competing proposals, and only
the most meritorious survive. The successful proposals are modified to reflect the critique of the advisory council and are advertised to the scientific
community in the NIH Guide.1 Interested investigators then compete to participate in the trial on the
basis of a specific trial design, past success in trials
of a similar nature, and a plan for recruiting patients
into the trial. A review committee is convened, and
the best groups are chosen. Before any funds are
awarded, NIH staff members seek final approval
of the program from their advisory councils.
The selected investigators meet, debate, and finally agree on a trial design that will answer the clin-
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ical questions that have been posed in a way that
adheres to best practices. Once the investigators
have what they believe to be an optimal trial design,
a committee of independent investigators reviews
and critiques the specific proposal. This is not a
rubber stamp but a tough review. Every point of the
trial design is examined closely. More often than
not, aspects of the trial need to be rethought to ensure that the data obtained will be clinically useful
and that the trial will provide the greatest margin of
safety for the patients who will be the research subjects. I know that these committees are tough; I have
had a number of proposed research trials sent back
for redesign and some scrapped altogether. Everyone involved takes the job — designing a trial that
advances the art while ensuring patient safety —
very seriously.
When the pretrial review ends, the ongoing review begins. Once the trial has been approved, the
NIH appoints a data and safety monitoring board
that oversees the trial as it is performed. This body
provides another layer of review to ensure that the
scientific questions are valid, that the patients in the
trial receive appropriate treatment, and that the results that emerge as the trial proceeds are analyzed
to make certain that the level of risk incurred by
participants remains acceptable as new knowledge
develops both within and outside the trial. Some
of the issues raised by the fact that research subjects are also patients are debated by Miller and
Rosenstein2 and by Grunberg and Cefalu3 in this
issue of the Journal.
After the successful completion of these multiple levels of review (Fig. 1), another review process
is held at the local level before the investigators can
actually start the work. Individual investigators prepare protocols and consent forms for their institutional review boards (IRBs). Each IRB examines the
protocol to be sure that the information to be
gleaned from the trial is worth the risk to the sub-
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Scientific community
Idea for research trial
Nonmeritorious ideas
rejected
NIH staff
Refines idea and prepares report
Nascent Idea
NIH Advisory Council
Many ideas rejected
Examines multiple ideas
Advises staff on importance
RFAs posted for investigators
Investigators respond
Review committee evaluates
Investigator Competition
Proposals returned to Advisory
Council for 2nd level of review
Investigators not funded
Investigators funded
Investigators Write Protocol
Investigators meet and
write definitive protocol
Revisions
Protocol reviewed by protocolreview committee
Final protocol
Data safety and monitoring board
Initial and ongoing review
Implementation Phase
IRB approval and
monitoring at each site
Trial
Figure 1. Process of Design, Review, and Approval of Clinical Trials.
NIH denotes National Institutes of Health, RFA request for applications, and IRB institutional review board.
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editorials
jects who will be participating in it. In the case of
patients in the intensive care unit, who are often
unable to participate in consent, there are special
considerations, as noted by Karlawish4 in this issue
of the Journal. The IRB also ensures that the risks
are clearly spelled out in the consent document that
the patients, or their surrogates, will sign as they
complete the transition from patients to patientsubjects. Only when IRB approval is obtained can
the trial begin.
A trial that makes it through these multiple levels of scrutiny must have merit. The process is designed to ensure that the question to be answered
is a clinically meaningful one, that equipoise exists,
and that the patients participating in the trial are
fully informed about the risks and benefits of that
participation. At every level, reviewers are asked to
be sure that there is appropriate and adequate protection in place for the human subjects who volunteer to participate. The information derived from
the completed trials often sets the direction for clinical decision making for many years to come.
Thus, the recent action by the OHRP with respect to the trial of the Acute Respiratory Distress
Syndrome (ARDS) Network of the NHLBI is troubling. As reported by Steinbrook5 in this issue of
the Journal, the NHLBI, at the request of the OHRP,
has put on clinical hold an ongoing ARDS Network
trial and is reexamining a completed trial.6 The primary reason for stopping the research is the contention, by investigators not associated with the trial, that the patients in both the completed trial and
the ongoing trial have been and are subject to increased risk because one patient group did not receive and is not receiving care according to the “best
current standard of practice.”7
The NHLBI has taken these criticisms very seriously, commissioning an independent blue-ribbon
panel of five experts — four American and one Canadian — who examined both the completed and
the ongoing ARDS Network trials. The panelists
unanimously concluded that the trials were scientifically sound, that the results were important for
the critical care community, and that the concerns
that led to the placement of the trial on clinical hold
were not valid. There is always some cause for concern when results of different trials are compared,
but in the completed ARDS Network trial — a trial
comparing mechanical ventilation using lower and
higher tidal volumes — the mortality in the group
receiving the larger tidal volume (the group that did
less well) was similar to the mortality that would
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be expected on the basis of the known severity
of their illness. This finding vitiates the argument
that patients in the completed trial were put at increased risk.
Although the NHLBI convened the blue-ribbon
panel, it did so with the advice and consent of the
OHRP. On receiving and reviewing the report of
these experts, Dr. Claude Lenfant, director of the
NHLBI, called the OHRP to say that he wanted to
restart the trial. He was told to keep it on hold. Subsequently, the OHRP sent a 29-page letter to the institutions participating in the ARDS Network requesting reams of data concerning the original
ARDS Network trial. As of this writing, the uncompleted trial is still on hold.
This series of events represents more than a
spat between the NHLBI and the OHRP. The action
by the OHRP has far-reaching implications for all
government-sponsored clinical research. If someone somewhere is unhappy with the design of a clinical trial, he or she could conceivably stop that trial
by complaining to the OHRP that it, as designed,
places the human subjects involved at increased
risk. This foray into the scientific review of a protocol represents new territory for the OHRP.
The role of the OHRP is to ensure that the process of research is carried out in accordance with
statute and regulation.8,9 The office oversees the
function and performance of individual IRBs and
the process of informed consent, and it investigates
when there is reason to believe that procedures with
respect to the protection of human subjects from
risks associated with research have not been appropriately followed. The OHRP has done much
to restore confidence in the system of IRB review
and to foster the integrity of the clinical-research
system.10
The NIH has an established record of designing, reviewing, and monitoring clinical trials; it has
the scientific expertise and the staffing to assume
responsibility for the appropriateness of trial design.
If there is concern about the safety of human subjects that derives from the conduct of the trial, rather than from the design of the research, the OHRP
should investigate the complaint. Concern about
the safety of human subjects that derives from the
design of the trial is an issue for the NIH. These are
separate and distinct roles.
When there are legitimate disagreements among
members of the scientific community about trial design with respect to the safety of the human subjects enrolled in the trials, the NIH and the OHRP
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should develop mechanisms to assess the validity of
these disagreements and to act accordingly. The
methods used to resolve the dispute must be well
defined, transparent, and time-sensitive. As a case
in point, more lives could well be lost because of
the extended interruption of the ARDS Network
trial by the OHRP and the resultant delay in getting
critical new information to the scientific community than would be saved through a redesign of the
trial. The OHRP and the NIH should use their distinct strengths to further the common goal of accruing the knowledge we need to deliver the best care
to our patients.
Dr. Drazen serves as a member of the National Heart, Lung,
and Blood Institute Advisory Council.
1. Office of Extramural Research. NIH guide for grants and con-
tracts. Bethesda, Md.: National Institutes of Health, 2003. (Accessed
March 14, 2003, at http://grants1.nih.gov/grants/guide/index.html.)
2. Miller FG, Rosenstein DL. The therapeutic orientation to clinical trials. N Engl J Med 2003;348:1383-6.
of
medicine
3. Grunberg SM, Cefalu WT. The integral role of clinical research
in clinical care. N Engl J Med 2003;348:1386-8.
4. Karlawish JHT. Research involving cognitively impaired adults.
N Engl J Med 2003;348:1389-92.
5. Steinbrook R. How best to ventilate? Trial design and patient
safety in studies of the acute respiratory distress syndrome. N Engl J
Med 2003;348:1393-401.
6. The Acute Respiratory Distress Syndrome Network. Ventilation
with lower tidal volumes as compared with traditional tidal volumes
for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med 2000;342:1301-8.
7. Eichacker PQ, Gerstenberger EP, Banks SM, Cui XZ, Natanson
C. Meta-analysis of acute lung injury and acute respiratory distress
syndrome trials testing low tidal volumes. Am J Respir Crit Care Med
2002;166:1510-4.
8. Assurances and IRB registration. Rockville, Md.: Office for
Human Research Protections, 2003. (Accessed March 14, 2003, at
http://ohrp.osophs.dhhs.gov/irbasur.htm.)
9. Compliance oversight. Rockville, Md.: Office for Human Research
Protections, 2002. (Accessed March 14, 2003, at http://ohrp.osophs.
dhhs.gov/compovr.htm.)
10. Putney SB, Gruskin S. Time, place, and consciousness: three
dimensions of meaning for US institutional review boards. Am J
Public Health 2002;92:1067-70.
Copyright © 2003 Massachusetts Medical Society.
Aldosterone Blockade and Heart Failure
Mariell Jessup, M.D.
In the fall of 1999, a multicenter, randomized trial
examining the effect of spironolactone on morbidity and mortality among patients with severe
heart failure was published in the Journal.1 The
Randomized Aldactone Evaluation Study (RALES)
proved that antagonism of aldosterone had an important role in the management of heart failure,
even in patients taking angiotensin-converting–
enzyme (ACE) inhibitors. In addition to reducing
mortality by 30 percent, small doses of spironolactone resulted in an improvement in ventricular function and enhanced exercise tolerance.2 The rates of
death from progressive heart failure and sudden
death from cardiac causes were both diminished
by an old, inexpensive medicine. This remarkable
study has led to intensified research into the mechanisms whereby aldosterone blockade benefits
patients with heart failure, to widespread use of
spironolactone in a range of patients with heart failure, and to a new trial involving a novel aldosterone
antagonist, eplerenone.3 Now is a good time to review the reasons why aldosterone blockade may
be effective and the types of patients in whom it
should be used.
Aldosterone was originally thought to be important in the pathophysiology of heart failure only insofar as it increased the retention of sodium and
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the loss of potassium. It was also believed that optimal doses of ACE inhibitors would suppress the
production of aldosterone, since angiotensin II is a
potent stimulus for adrenal aldosterone secretion.
In fact, both angiotensin II and aldosterone ultimately escape the effects of long-term ACE inhibition,
with aldosterone levels showing a more pronounced
rebound.4 Plasma aldosterone concentrations may
reach 20 times the normal level in patients with heart
failure, because of both increased production and a
decreased rate of hepatic clearance. In addition to
being produced by the adrenal glands, aldosterone
is synthesized by human vascular cells and has a
number of adverse effects on the vasculature.5 Sustained elevations of angiotensin II and aldosterone
concentrations induce abnormal vasomotor reactivity and baroreceptor responsiveness by promoting
endothelial dysfunction and oxidative stress. Moreover, intense interest has focused on the role of aldosterone in promoting organ fibrosis. A survival
benefit among patients receiving spironolactone in
RALES was associated with a reduction in the concentrations of serum markers of collagen synthesis.
These and numerous other findings, as reviewed recently,6 emphasize the importance of tissue collagen turnover and fibrosis in heart failure as critical components in cardiac remodeling.
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