Schizophrenia Bulletin vol. 32 no. 1 pp.
37–41, 2006
doi:10.1093/schbul/sbj004
Advance Access publication on September 28, 2005
The Relevance of Empirical Research in Bioethics
Franklin G. Miller1–3 and David Wendler3
2
Clinical Center, National Institutes of Health, Building 10,
Room 1C118, Bethesda, MD 20892-1156; 3Department of
Clinical Bioethics, National Institutes of Health
Empirical research related to ethical issues in clinical re-
search has grown dramatically in recent years. However,
little attention has been devoted to the ethical relevance
of the findings from this research. In order to examine
the value and limitations of ethics-related empirical re-
search, we discuss 3 case studies involving research with
stored biological samples, placebo-controlled trials, and
the idea of the therapeutic misconception.
Key words: research ethics/empirical ethics research/
stored samples/placebo-controlled trials/therapeutic
misconception
Introduction
Empirical research has been part of ethical reflection on
clinical research for at least the past 30 years. For exam-
ple, sociologist Bernard Barber and colleagues published
in 1973 the results of extensive survey research concern-
ing the practice of medical experimentation relating to
‘‘two key issues in the treatment of human research sub-
jects: informed consent and the proper risk-benefit
ratio.’’1(p11) The volume of empirical research on ethical
issues relating to clinical research has grown dramatically
in tandem with the growth of bioethics as a discipline,
especially its development within academic medical cen-
ters and the increasing tendency for bioethics research to
be published in medical journals. The demands for pro-
fessional advancement largely explain the increasing vol-
ume of ethics-related empirical research, as publication of
empirical research in peer-reviewed high-impact journals
is a key to professional success. Nevertheless, the ethical
significance of this research—the way in which it can con-
tribute to understandings of ethical issues in biomedical
research—is not transparent and has not received the at-
tention it deserves.
1
To whom correspondence should be addressed; phone: 301-
435-8719, fax: 301-496-0760, e-mail: fmiller@nih.gov.
Ó The Author 2005. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: journals.permissions@oxfordjournals.org.
37
Ethics-related empirical research faces a basic philo-
sophical challenge. Since at least the time of Hume
(1711–1776), moral philosophers have argued that there
is a distinction between descriptive propositions stating
matters of fact about human conduct and normative pro-
positions stipulating how people ought to behave.2(p521)
As a matter of logic, normative conclusions cannot be
derived from purely descriptive premises. Since empirical
research yields descriptive propositions about practices,
beliefs, and attitudes, what (if any) relevance can it
have to pressing ethical issues?
Ethical inquiry and debate often rely, at least implicitly,
on empirical propositions that frame the context of moral
judgment and contribute to the justification of these
judgments. For example, informed consent is a basic re-
quirement of human subjects research, grounded in the
principle of respect for persons. Empirical research can
assess various aspects of informed consent for clinical
research, including whether subjects have the requisite un-
derstanding of the research in which they are participat-
ing. Such research may be conducted to determine if
participants in randomized controlled trials (RCTs) com-
prehend the fact that their treatment will be selected by
a random process and not a medical judgment of what
is best for them.
Suppose it is found that 75% of subjects in a variety of
RCTs understand random selection of treatment. This
poses further ethical issues. Should we feel satisfied
that most subjects understand randomization or dis-
mayed that a substantial proportion do not? Empirical
research generates this question but is not equipped to
answer it. The answer depends on the normative issue
of what is considered necessary to give informed consent
to an RCT, which may vary depending on the nature of
the study in question. Nevertheless, those who are dissat-
isfied with these survey results may undertake valuable
empirical research to determine whether innovative
methods of informing prospective subjects of RCTs
can improve their understanding of randomization and
other elements of informed consent. This inquiry might
itself take the form of an RCT to evaluate the innovative
method in comparison with standard practice.
Ethical assessments of the design and conduct of clinical
research by means of survey research and evaluative re-
search aimed at improving the ethical conduct of clinical
research are important examples of potentially valuable
F. G. Miller & D. Wendler
ethics-related empirical research. In what follows, we will
examine 3 case studies with the aim of illustrating the value
and limitations of empirical research as it relates to the
ethics of clinical research.
Research With Stored Biological Samples
As mentioned above, respect for persons is a basic norm
governing research with human subjects, and respect for
persons implies that investigators typically should obtain
individuals’ informed consent before enrolling them in re-
search. Yet it is a truism of research ethics that no indi-
vidual can possibly understand all that there is to know
about even the most basic research study. This fact raises
the question of what information individuals should be
provided in order for them to give valid informed con-
sent. Most commentators agree that investigators should
begin to answer this question using the ‘‘reasonable per-
son’’ standard, that is, investigators should provide to
prospective subjects the information that the reasonable
person would want to know to decide whether to enroll in
the study in question. Empirical research can help to de-
termine what information the reasonable person wants,
in effect narrowing the is/ought gap. Research with stored
biological samples provides an illustrative example.
With increases in genetic technology, research with bi-
ological samples has become increasingly popular and im-
portant. What information should investigators provide
individuals prior to obtaining their sample to be used for
future research? Some commentators argue that as long
as the risks are sufficiently low, for example, when samples
are anonymous, informed consent is unnecessary.3 Others
argue that prospective subjects should be provided a list of
various options, such as which diseases will be studied and
how the samples will be stored, so they can make a mean-
ingful decision whether to enroll in the research.4–6
Current standards indicate that the determination of
which side is right in this debate depends, in large
part, upon what information the reasonable person
would want to make this decision. Allowing individuals
to control the use of their samples shows respect for them
as persons. However, the ethical principle of respect for
persons alone does not determine how many or which
choices individuals should be offered. To make this de-
termination, it is important to assess which choices indi-
viduals want to make. For instance, the widely endorsed
recommendation to offer individuals multiple check-off
options for different diseases is based on the assumption
that individuals find this choice meaningful.
Numerous studies have been conducted to assess indi-
viduals’ views regarding informed consent for research
with biological samples.7–12 Using hypothetical scenarios,
1 study suggests that individuals want to control whether
their samples are used for research but do not want to de-
cide which diseases can be studied using their samples.10 A
study of oncology research participants found that the
38
vast majority would allow their biological samples to
be used to study any disease.11 A study of over 1,000 re-
search subjects found that more than 85% authorized un-
limited future research use of their biological samples
when given the opportunity to do so.12
These data reveal that the vast majority of individuals
do not want to control which diseases are studied using
their samples; nor do they want to control which re-
searchers are allowed to use their samples for future re-
search. These empirical findings have been cited in
support of the proposal that it would be permissible to
offer individuals a simple binary choice of allowing or
refusing future research on their stored biological sam-
ples.12 Essentially, it seems that this is the relevant choice
according to the reasonable person standard.
Like all empirical findings, these data do not definitively
settle the issue. First, as with any meaningful area of hu-
man endeavor, empirical data will never show that abso-
lutely everyone agrees on anything. Hence, empirical data,
no matter how convincing, will leave us with the question
of how we should treat the minority who do not, according
to our data, agree with the views of the majority. This is not
an issue that can be answered by the data themselves. In-
stead, ethical analysis is needed to assess the importance of
the competing claims, and these will vary depending upon
the issue in question. Is a fundamental right of the minor-
ity in question? Or is it more a matter of convenience?
Placebo-Controlled Trials
In the past 10 years a lively debate has developed over the
ethics of placebo-controlled trials. There are sound meth-
odological reasons for placebo controls for the evaluation
of new treatments in certain disorders, despite the exis-
tence of proven effective treatment for the disorder in
question.13 Placebo-controlled trials are common in psy-
chiatric disorders for a variety of methodological reasons,
including the fact that available treatments are generally
aimed at ameliorating symptoms; they are assessed
according to subjective outcomes; and RCTs demon-
strate high rates of placebo response.14 Moreover, active-
controlled trials designed to evaluate the equivalence or
noninferiority of an experimental treatment compared
with a standard treatment are subject to problems of in-
ternal validity or assay sensitivity.15 Nonetheless, patients
randomized to placebo must forgo medically indicated,
proven effective pharmacologic treatment. Many com-
mentators consider this to be unethical.16–17 Other com-
mentators assess the use of placebo controls in trials of
treatment for depression and anxiety disorders (and a
variety of chronic conditions in other areas of medicine)
as no different in principle than the use of other research
procedures that carry risks to subjects with no prospect of
benefit to them.13, 18
One issue relevant to this debate is whether research
participants randomized to placebo controls are exposed

to undue risks of harm. The risks of placebo assignment
can be assessed by empirical research. The risks of greatest
concern in the case of depression are suicide and at-
tempted suicide. Also important is whether patients ran-
domized to placebo fare worse than those receiving
experimental or standard treatment with respect to symp-
toms of depression. A meta-analysis of antidepressant tri-
als in the U.S. Food and Drug Administration database,
encompassing thousands of patients, found that those de-
pressed patients receiving placebo were not at signifi-
cantly greater risks of suicide or attempted suicide.19
With respect to symptomatic outcomes, patients random-
ized to placebo in these antidepressant trials experienced
a mean 31% symptom reduction during trial participa-
tion, as compared with 41% symptom reduction for
patients who received investigational or active com-
parator drugs. Thus, it appears that, in the aggregate, de-
pressed patients receiving placebo controls in short-term
trials are not made worse off or disproportionately disad-
vantaged as compared with those receiving pharmaco-
logic treatment.
These data inform the debate, but they do not settle it.
Knowing the consequences of placebo assignment does
not determine whether the observed differences between
placebo and active medication are ethically acceptable.
This difference in risks and benefits is open to assessment
on ethical grounds. Here, again, we face the gap between is
and ought, between descriptive data and normative con-
clusions. More important, from an ethical perspective,
these data relate to only a single dimension of the ethical
dispute: risks of harm from placebo assignment. A key is-
sue in contention is whether it is wrong per se to random-
ize patients to placebo in the face of proven effective
treatment, owing to the therapeutic obligation of physi-
cians and the rights of patients to receive competent med-
ical care. Some commentators, invoking the principle of
clinical equipoise, condemn such placebo-controlled
trials.17 For example, Weijer has recently claimed that
‘‘placebo-controlled trials in the context of serious ill-
nesses such as depression or schizophrenia are ethically
egregious precisely because no competent physician
would fail to offer therapy to a patient with the condi-
tion.’’20(p10) Others argue that this position is fundamen-
tally mistaken because it confuses the ethics of clinical
research with the ethics of medical care.18, 21 This dispute
concerns the basic ethical norms that should govern clin-
ical trials. Empirical research cannot determine whether it
is wrong to conduct placebo-controlled trials despite the
existence of proven effective treatment, though it may
play a subordinate role in the ethical analyses and argu-
ments in support of the contending positions.
The Therapeutic Misconception
Empirical research may serve bioethics by posing issues
of ethical concern deriving from the interpretation of re-
The Relevance of Empirical Research in Bioethics
search results. Therapeutic misconception has become
a term of art in research ethics, denoting the propensity
of patient/subjects enrolled in RCTs to confuse treatment
provided in these studies with the situation of routine
medical care, in which physicians recommend treatment
based on a judgment of what is best for the particular pa-
tient.22 Appelbaum and colleagues coined this term to de-
scribe the findings of empirical research on the informed
consent process for psychiatric patients enrolled in
RCTs.23 It is worth noting that the initial formulation of
the idea of the therapeutic misconception (TM), prompted
by reflection on ethics-related empirical research, was
guided by ethical thinking relating to RCTs. The authors
appealed to the work of Fried, who contrasts the design of
the RCT with the standards of ‘‘personal care’’ character-
istic of clinical medicine.24 The former activity is designed
to generate scientific knowledge about the efficacy and
safety of treatments; the latter is designed to do what is
best for individual patients. Recognizing the fundamen-
tally different contexts of clinical trials research and med-
ical therapy raises the question of whether patient/subjects
understand that they will be treated differently in research
than in medical care. Appelbaum et al. offer the following
example of a patient/subject who manifested the TM:
In the same study, another subject was a twenty-
five-year old woman with three years of college. At
the time of the interview, she had minimal psychiat-
ric symptoms and her understanding of the research
was generally excellent. She recognized that the pur-
pose of the project was to find which treatment
worked best for the group of patients. She sponta-
neously described the three groups, including the
placebo group, and indicated that assignment would
be random.. When asked directly, however, how
her medication would be selected, she said she had
no idea. She then added, ‘‘I hope it isn’t by chance,’’
and suggested that each subject would probably re-
ceive the medication she needed.23 (pp 22)
Identification of the TM, based on empirical research,
leads to a number of vexing ethical questions. What dif-
ference does it make that some patient/subjects harbor
TMs about research participation? Does evidence of
the TM imply that informed consent was not obtained?
Appelbaum et al. raise another key ethical question about
their findings that continues to bedevil the ethics of clini-
cal research: ‘‘Should we do anything about the therapeu-
tic misconception?’’23 (pp 22) It is a basic logical principle
of moral philosophy, propounded by Kant, ‘‘that ought
implies can.’’ It makes sense to argue that we should at-
tempt to dispel the TM only if there is reason to think that
we can do so. Appelbaum and colleagues have contrib-
uted to an answer to this question by building into their
initial research an ‘‘augmented informational process’’
using a ‘‘neutral discloser,’’ not involved in the RCTs un-
der examination, who instructed participants prior to
39
F. G. Miller & D. Wendler
enrollment about ‘‘key methodologic aspects of the
research project, especially methods that might conflict
with the principle of personal care.’’23 (pp 23) It was found
that subjects exposed to this neutral and augmented dis-
closure had a better understanding of important aspects
of the research design, including randomization, use of
placebo, and protocol-defined limitations on treatment.
From a policy perspective, whether we ought to require
an informed consent process that is designed to obviate
therapeutic misconceptions depends, in part, on an em-
pirical issue: How prevalent is the TM? Although bioeth-
icists appear to have presumed that the prevalence is high,
it is only recently that any systematic data have been
available beyond the small studies conducted in the
1980s on psychiatric patient/subjects. Appelbaum and
colleagues have attempted to answer this question by
reporting data on interviews with 225 research partici-
pants in 44 studies across a wide range of conditions.25
A fundamental methodological issue related to assess-
ing the prevalence of the TM is how to measure this phe-
nomenon. There is no standard, operational definition of
what constitutes a TM; nor are there standard assessment
tools for determining its presence or measuring the extent
to which a given research participant manifests the TM.
With respect to definition, Appelbaum et al. identify 2
variants of the TM, which they call TM1 and TM2.
TM1 occurs ‘‘when participants express an incorrect be-
lief that their individualized needs will determine assign-
ment to treatment conditions or lead to modification of
the treatment regimen.’’25 (pp 2) TM2 occurs ‘‘when partic-
ipants offer an unreasonable appraisal of the nature or
likelihood of medical benefit from participation in the
study, due to a misperception of the nature of the re-
search enterprise.’’25 (pp 2) Whether these 2 forms of the
TM tap the same phenomenon is an important methodo-
logical issue with ethical implications. In their research,
Appelbaum et al. found that 31% of the subjects mani-
fested TM1 and 51% manifested TM2, with 62% judged
to have a TM on 1 or both variants. It is obvious that
how the concept is defined makes a big difference in deter-
mining its prevalence. TM1 certainly captures the core
concept of confusing research with therapy. It is not as
clear that TM2 constitutes the same misunderstanding.
More work is needed to refine and standardize the def-
inition of the TM, to develop assessment tools to reliably
identify this phenomenon, and to conduct systematic
studies across different types of clinical trials with differ-
ent groups of patient/subjects. Nevertheless, the policy
question of whether methods should be developed and
implemented to dispel the TM remains pressing. Focus-
ing only on TM1, the finding that 31% of subjects man-
ifested the TM appears ethically troubling. But the ethical
significance of this concern remains open to inquiry. Joffe
and Weeks assert that ‘‘the therapeutic misconception ar-
guably constitutes the most important threat to the val-
idity of informed consent to research.’’26 (pp 1847) Does it
40
follow that any manifestation of the TM among research
participants invalidates their consent to research, thus
making their enrollment unethical? In other words, is ac-
curate understanding and appreciation of the differences
between participating in clinical trials and receiving med-
ical care necessary for informed consent?27 Since the TM
appears to be a matter of degree, what level or extent
of this misconception undermines informed consent?
How should investigators in the informed consent pro-
cess, or consent monitors, assess the presence of TMs
among prospective subjects and intervene to dispel
them? There is no consensus on how to answer these eth-
ical questions. Further empirical research can inform the
answer to this last question, but further conceptual re-
search on the ethical significance of the TM and, more
broadly, the meaning of informed consent to clinical re-
search will be needed to address the other questions.
Conclusions
Empirical research can contribute importantly to ethical
inquiry concerning clinical research. The potential value
of this research depends on the ethical significance of the
questions asked, the suitability of the methods to answer
the questions, and interpretation of the ethical import of
the findings. Ethical analysis can and should inform each
of these aspects of empirical research. However, regard-
less of the quality of ethics-related empirical research,
there are limits to what such research can accomplish.
At the end of the day, the gap remains between what
is the case and what ought to be.
Acknowledgments
Our work on this article was supported by the Clinical
Center of the National Institutes of Health and the
Intramural Research Program of the National Institute
of Mental Health (FGM). The opinions expressed are
ours and do not necessarily reflect the position or
policy of the National Institutes of Health, the Public
Health Service, or the Department of Health and
Human Services.
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