The Nuremberg Code recently celebrated its 50th birthday, marking the progress
that has been made in ensuring respect for human rights both within and beyond
the context of medical research . Today, many journal editors will refuse to
consider manuscripts that have not undergone formal review by an independent committee,
and virtually none will publish results that were procured without the explicit
informed consent of the subjects. In one sense, therefore, the bioethics movement
of the past several decades seems to have scored a resounding victory.
In another sense, however, the rapid pace of medical research and the increasing
effectiveness of medical interventions have only intensified the ethical dilemmas
that physicians encounter in clinical research. The intensive care environment,
in particular, has several characteristics that provide especially difficult challenges
to the standard requirements of informed consent for research. I will highlight
three features of this environment that may call for innovative or alternative
approaches to both study design and the process of informed consent to both respect
the rights of the research subject and permit the continued accrual of medical
First, many trials performed in critical care medicine involve experimental treatments
that have the potential to be life saving. Patients who are eligible for studies
in the intensive care unit (ICU) are often extremely ill, and standard therapy
may have little or nothing to offer. While clinicians may be able to take a dispassionate
stance and insist that from the perspective of the medical scientist there is no
evidence that the experimental therapy is superior to conventional treatment, the
patient or family may have a very different impression. They may hold the firm
belief that the experimental treatment offers the only significant hope for the
patient's survival. From their perspective, randomization may not represent the
process of choosing between two equally effective alternatives, but rather may
be a seen as a coin flip between a chance for survival and an almost certain death.
Indeed, there is evidence that families misperceive the process of randomization
as a mechanism for triaging patients when a therapy is too scarce to offer to
everyone . This feature of ICU research creates intense ethical conflicts for
clinical researchers, and will be explored in more detail below.
The second characteristic aspect of intensive care research that leads to unique
ethical issues is the fact that very few of the potential research subjects are
capable of engaging in a discussion of informed consent. Either patients are too
heavily sedated to permit their participation in deliberations about their care,
or they are acutely ill and decisions about inclusion into trials need to be made
on an emergency basis (eg trials of alternative modes of performing cardio-pulmonary
resuscitation). The former problem has had a relatively straightforward solution
in the USA, where both ethics and law have almost uniformly recognized the legitimacy
of surrogates to make medical decisions for incompetent patients, including in
most cases providing consent for therapeutic research. This is often not the case
in Europe, where surrogate decision-making remains more controversial .
The difficulties of performing research on emergency interventions was recently
recognized in the USA by the Department of Health and Human Services, which responded
by creating an emergency exemption to informed consent in situations where the
experimental intervention must be introduced emergently and where the patient is
both unable to consent and surrogate decision-makers are not available . This
exemption has been strongly opposed by some critics as a dangerous precedent away
from an uncompromising commitment to informed consent for research, but several
trials utilizing this intervention are currently under way .
The third characteristic of the critical care environment that places unique demands
upon research is the often rapidly changing and developing nature of the technologies
being tested. Many ICU interventions involve complex technical procedures or sophisticated
mechanical devices [eg extracorporeal membrance oxygenation (ECMO), continuous
venovenous hemofiltration (CVVH), high-frequency oscillatory ventilation (HFOV)]
that have a steep learning curve and that undergo almost continual evolution through
the 'tinkering' of skilled and creative clinicians. This creates an inevitable
tension in the efforts of researchers when they want to show that these new techniques
are an improvement over previous therapies. On the one hand, it is important that
the clinicians develop these interventions to the point where they feel they have
mastered the most critical technical challenges and have overcome the major hurdles
of applying the technology to critically ill patients. On the other hand, it is
important that the clinicians not miss a 'window of opportunity' for rigorously
comparing these new technologies against standard therapy in a formal clinical
trial, before the technologies become uncritically and widely accepted into clinical
This inherent tension is compounded by the need to standardize the treatments in
both the experimental and control arms of a clinical trial. Consider, for example,
recent clinical trials of neonatal ECMO in the USA and the UK. Each of these trials
took several years to complete. During these intervals, ECMO technology underwent
continuous evolution, ranging from developments in catheter design to alternatives
in anticoagulation to new surgical approaches (such as venovenous ECMO as an alternative
to venoarterial, repair rather than ligation of the carotid artery). Similarly,
during the time-frame of these trials there were major innovations in nonECMO
interventions, such as the emergence of HFOV, nitric oxide therapy, and permissive
hypercarbia. During the period of the trials, centers performing under protocol
had to accept a virtual freeze on any inclination to either tinker with their approach
to ECMO or to introduce any modifications to the 'control' protocols. This moratorium
on innovation impacted the trials in two major respects: first, by the end of the
trials, the families of children in the control arm could no longer be assured
that they were in fact receiving the best standard clinical care (since centers
not involved in the protocol had progressed to using alternative strategies); second,
evolution in the technology of ECMO itself was sufficiently different by the end
of the studies that the results of the trials could truthfully only be said to
apply to a form of ECMO that was already obsolete. The moral of the story is this:
when both the experimental therapies and the standard therapies are in rapid evolution,
standard approaches to comparing them through formal clinical trials are often
too time-consuming, leading to restrictions on clinical innovation and results
that are already obsolete by the time they are published.
Each of these three considerations raises interesting questions about how to modify
our approach to research in the ICU in ways that will continue to respect the fundamental
principles of Nuremberg while continuing to allow for the advancement of medical
knowledge. In the remainder of my comments, I will return to the first issue cited
above, namely the conflicts that occur when experimental therapies are potentially
Perhaps the most fundamental ethical dilemma in medical research concerns the potential
for conflict of interest between the roles of the physician as clinician versus
the physician as scientific investigator. Acting in the role of clinician, the
physician's highest priority is the welfare of the individual patient. The goals
of the scientific investigator, on the other hand, are focused upon the acquisition
of medical knowledge in order to benefit future patients. One recent paper characterized
this dichotomy in terms of 'individual ethics' versus 'collective ethics', or
'doing what is best for current subjects in the trial versus doing what is best
for future patients who stand to benefit from its results' .
How does the clinician resolve the conflict between these divergent roles? One
suggestion has been to insist that the clinician be in a state of equilibrium,
or 'equipoise', regarding the relative efficacy of the various treatments being
studied. In other words, if the clinician is completely undecided as to which of
the treatments is best, then there is no conflict of interest in choosing between
these treatments by the 'flip of a coin'.
This standard, described as 'personal equipoise', has long been recognized as being
too stringent. To begin with, virtually all clinical investigators enter into clinical
trials with the belief that their intervention is superior to existing treatments.
Otherwise, why would they spend the enormous amounts of time and energy involved
with performing the studies necessary to demonstrate this superiority? Furthermore,
based upon their personal experience and individualized reading of the literature,
clinicians frequently have strongly held opinions about which of the alternative
interventions is the most effective, even if the published evidence is far from
conclusive. Under the personal equipoise standard, these clinicians would be ethically
barred from participating in randomized comparisons of these interventions.
Benjamin Freedman is generally credited with proposing an escape from this dilemma,
based upon the concept of 'clinical equipoise' . Clinical equipoise exists when
there is uncertainty about the relative efficacy of alternative treatments within
the medical community as a whole. Freed-man claimed that a state of clinical equipoise
is necessary for physicians to ethically enroll patients in clinical trials. It
is not necessary for a clinician to be in personal equipoise in order to enroll
a patient, Freedman argued, so long as there is genuine uncertainty within the
medical community, ie so long as there is a state of clinical equipoise.
The concept of clinical equipoise has been very useful in relieving the ethical
tensions between clinicians and investigators in most types of clinical trials.
To give an example, if I believe that a new β -blocker offers advantages over those
currently on the market, I can, with a clear conscience, enroll my patients in
a randomized trial that compares the new medication with another that is standardly
available. I simply explain to my patients that, even though I have a hunch that
the new medication will eventually prove to be better than the alternatives, they
should be willing to have their therapy determined by a flip of the coin, since
there is as yet no convincing evidence to support my belief in the superiority
of the new drug.
The concept of clinical equipoise is less convincing, however, when it is used
to justify the randomization of treatments that have the potential to be life saving.
I will use the history and development of neonatal ECMO as a paradigmatic type
of ICU research that also provides an excellent case study for exploring this issue
ECMO emerged in the 1960s when development of the membrane oxygenator permitted
the use of cardiopulmonary bypass for periods of more than a few hours. Although
early efforts in the use of ECMO for adults with acute respiratory failure were
disappointing, interest persisted in the use of ECMO to treat neonatal respiratory
failure. Robert Bartlett therefore used this new therapy to treat 16 critically
ill infants, and reported six survivors. Encouraged by these initial results, Bartlett
continued to develop the technology, and by 1980 achieved 75% survival in patients
judged to have a 95% mortality when managed with conventional therapy . Despite
this success, many remained skeptical about the effectiveness of ECMO in the absence
of a formal clinical trial. Bartlett realized the need for a rigorous comparison
of ECMO against standard therapy, but was concerned about denying some patients
a therapy he viewed as potentially life-saving.
Should Bartlett have relied upon Freedman's concept of clinical equipoise, and
proceeded with a randomized clinical trial comparing ECMO against standard therapy?
In 1980 there was clearly uncertainty within the medical community about the relative
benefits of ECMO, and indeed most neonatologists were biased against it. Yet I
believe that Bartlett was correct in viewing clinical equipoise as an inadequate
justification for proceeding with a traditional randomized comparison of ECMO against
standard therapy, for at least two reasons.
First, imagine what doctor-patient relationships would be like if doctors always
took clinical equipoise seriously. Imagine a physician saying, 'My personal opinion
would be to begin antibiotics for possible sepsis in a patient with your signs
and symptoms. Nevertheless, since there is disagreement about this in the medical
literature and the medical community more generally, I will decide whether or not
to start you on antibiotics by flipping a coin'. Such a doctor would probably command
little respect from his patients or colleagues, yet this is precisely what is demanded
of the doctor when enrolling patients in clinical trials.
Second, the structure of randomized clinical trials often requires them to continue
beyond the point at which clinical equipoise has already dissolved. Consider a
hypothetical trial that, based on power calculations, is scheduled to enroll 1000
patients. Suppose that almost all of the patients have been enrolled, and that
the P value is already well below 0.05. Based upon standard research procedure,
however, the investigators are forbidden from analyzing the data until all of the
patients have been enrolled (I am here ignoring the possibility of early stopping
rules). Assuming that the outcomes from the few remaining patients do not have
the potential to raise the P value above the significance threshold, then all remaining
patients who are randomized into the control arm of the study will receive a treatment
that will soon be shown to be inferior to the alternative.
What ethical justifications could be offered to defend the randomization of these
remaining patients into the control arm of the study, other than a justification
(based upon a 'collective' rather than an 'individual' ethic) that sacrifices the
best interests of these patients in favor of producing knowledge that will benefit
future patients? While some patients may find this sacrifice acceptable for many
types of trials (eg the β -blocker study mentioned above), few would be willing
to risk their lives by not receiving the superior treatment, especially if the
value of their sacrifice was only to move the P value a little lower below the
level of 0.05.
Perhaps it was these types of concerns that led Bartlett to decide not to proceed
with a traditional randomized clinical trial in the evaluation of neonatal ECMO.
The approach that he adopted is one that has emerged within a growing literature
by statisticians who are sensitive to the ethical concerns that may arise in randomized
trials such as these [6,10,11,12,13,14]. They have developed a number of innovative
and intriguing alternatives to traditional randomized trials that seek to mitigate
the inherent tension between the goals of the physician as clinician and the goals
of the physician as scientific investigator. I believe these alternatives have
been underutilized in the design of clinical trials in critical care medicine,
and that the interests of individual patients have been unduly sacrificed to the
interests of medical knowledge and future patients. As one recent statistical review
of these alternative approaches concluded, 'when circumstances are appropriate,
the failure to exploit modern statistical methodology and information technology
is indefensible in present day clinical trials' .
Bartlett chose one of the more straightforward (and intuitively compelling) alternative
statistical techniques known as 'adaptive randomization'. Simply put, adaptive
randomization strategies alter the randomization scheme so that more patients are
assigned to the treatment that is proving to be more successful. These methods
are often described as 'play the winner' strategies, although it would be more
accurate to refer to them as 'play the leader'.
Bartlett's randomization strategy began with 'balanced' or 50/50 randomization
of the first patient to either conventional treatment or ECMO, with the randomization
of subsequent patients heavily weighted toward whatever therapy was proving more
successful. Unfortunately, by heavily biasing the randomization in this way, he
ended up with a very skewed distribution between the two treatments. Eleven patients
were assigned to ECMO, and all survived. Only one patient was assigned to conventional
therapy, and this child died .
This study illustrates that, when adaptive randomization is taken to an extreme,
it may produce results that, while perhaps statistically sound, are clinically
unconvincing. The Bartlett trial was therefore widely criticized, and in an editorial
that accompanied the published manuscript, a statistician and neonatologist from
Harvard claimed that a better study was needed before the superiority of ECMO could
be accepted .
Not surprisingly, however, when this same Harvard team met to design a better trial,
they faced the same ethical dilemma that had plagued Bartlett. In addition to Bartlett's
published experience, a national ECMO registry was also accumulating data that
showed impressive survival rates with ECMO. A 1988 review of 715 newborns treated
with ECMO, for example, demonstrated 81% survival with ECMO and indicated that
ECMO was statistically superior to any other treatment with a survival rate less
than 78.4% . Few neonatologists at that time could have argued that survival
rates of critically ill newborns managed without ECMO were anywhere close to 78.4%.
As a result, the Harvard team also decided to use an adaptive randomization design,
choosing only to be less extreme than Bartlett. In the Harvard design, patients
were randomized 50/50 to either ECMO or conventional treatment until there was
a fourth death in either arm of the study (Phase 1); at that point, all future
patients were randomized to the more successful arm, and this was continued until
statistical significance was achieved (Phase 2) .
Using this more conservative design, the Harvard study achieved more convincing
results. During Phase I, nine patients were assigned to ECMO and all survived.
Ten patients received conventional therapy; six survived and four died. With the
fourth death in the conventional arm, Phase II began. An additional 20 patients
were enrolled to receive ECMO; 19 survived and one died. At this point ECMO was
judged to be statistically superior to conventional therapy. In retrospect, four
patients died who might have survived if they had been offered ECMO. Nevertheless,
this was a smaller number than would have died if the trial had been designed with
traditional 50/50 randomization. To this extent, adaptive randomization was successful
in both demonstrating the superiority of ECMO and in reducing the total number
Given the ethical advantages of adaptive randomization designs, why are they not
used more frequently in the evaluation of potentially life saving therapies in
intensive care medicine? 'Adaptive methods should be used as a matter of course',
remarked statistician Weinstein in The New England Journal . 'It never pays
to commit oneself to a protocol under which information available before the study
or obtained during its course is ignored in the treatment of a patient' .
Despite endorsements like this, adaptive randomization, as well as other statistically
sound alternatives to the traditional randomized trial, continue to be utilized
rarely. Some have suggested that this bias is based upon a reluctance to take a
risk in the highly competitive process of grant proposals, but many factors are
probably involved .
The ECMO story itself provides a striking example of this prejudice against adaptive
randomization designs. In the early 1990s, the UK was considering whether to adopt
ECMO into its armamentarium of treatment for neonatal respiratory failure. After
considering all of the above evidence, clinicians in the UK concluded that the
superiority of ECMO to conventional management was still in doubt, and that a traditional
randomized controlled trial was needed before accepting ECMO for widespread use
in the UK. Between 1993 and 1995, 185 newborns were randomized into a traditional
trial of ECMO versus standard therapy. The trial was stopped early on the advice
of a data monitoring committee when preliminary evidence showed a clear advantage
of ECMO. Overall, 30 of 93 infants allocated to ECMO died, compared with 54 of
92 allocated to conventional care (P =0.0005) .
Certainly there are no grounds to impugn either the motives or the intentions of
the researchers from the UK who conceived and executed this trial. Nevertheless,
just as some have questioned whether clinical equipoise existed at the time of
the Harvard ECMO trial, I think it is fair to ask whether clinical equipoise existed
at the time of the UK ECMO trial, and whether the trial thereby met one of the
standard ethical requirements for clinical research . In any case, the UK trial
served to illustrate the bias that currently exists against accepting the results
of trials that employ adaptive randomization, and, by extension, any other alternatives
to the traditional approach.
The UK trial also raises questions about how we determine which treatments should
be considered 'experimental' and which 'control'. Given the evidence gathered from
clinical experience and research in the USA prior to 1993, a good case could have
been made for at least presuming the superiority of ECMO over conventional management.
If so, then perhaps patients who were eligible for the UK trial but whose families
refused to participate should have been offered ECMO as the 'control' treatment,
rather than so-called conventional therapy .
The development of ECMO has perhaps provided as many interesting questions and
insights into the process of study design and informed consent as it has into the
management of neonatal respiratory failure. The UK investigators have continued
this tradition by expanding upon their trial to explore the experiences of the
families who were involved to learn more about their attitudes toward informed
consent and alternative schemes of randomization [2,22,23]. ECMO has therefore
been a paradigmatic case study for many of the types of trials that have been and
will be performed in intensive care medicine. We should not lose the opportunity
to learn from these experiences, since, as Santayana observed, 'those who cannot
remember the past are condemned to repeat it'.