EDITORIAL
The Ethics of Clinical Research in the
Angell M. The ethics of clinical research
in the third world.
N Engl J Med
1997;337:847-9.
Marcia
Angell, M.D.
An essential ethical condition for a
randomized clinical trial
comparing two treatments for a disease is that there be no good
reason for thinking one is better than the other. (1,2) Usually,
investigators hope and even expect that the new treatment will be
better, but there should not be solid evidence one way or
the
other. If there is, not only would the trial be
scientifically
redundant, but the investigators would be guilty of knowingly
giving inferior treatment to some participants in the trial.
The
necessity for investigators to be in this state of equipoise
(2)
applies to placebo-controlled trials, as well. Only when
there is
no known effective treatment is it ethical to compare a
potential
new treatment with a placebo. When effective treatment
exists, a
placebo may not be used. Instead, subjects in the control
group
of the study must receive the best known treatment.
Investigators
are responsible for all subjects enrolled in a trial, not
just
some of them, and the goals of the research are always
secondary
to the well-being of the participants. Those
requirements are
made clear in the Declaration of Helsinki of the World
Health
Organization (WHO), which is widely regarded
as providing the
fundamental guiding principles of research involving human
subjects. (3) It states, "In research on man [sic], the
interest
of science and society should never take precedence over
considerations related to the wellbeing of the subject," and
"In
any medical study, every patient -- including those of a
control
group, if any -- should be assured of the best proven
diagnostic
and therapeutic method."
One reason ethical codes are unequivocal
about investigators'
primary obligation to care for the human subjects of their
research is the strong temptation to subordinate the subjects'
welfare to the objectives of the study. That is particularly
likely when the research question is extremely important and
the
answer would probably improve the care of future patients
substantially. In those circumstances, it is sometimes argued
explicitly that obtaining a rapid, unambiguous answer to the
research question is the primary ethical obligation. With the
most altruistic of motives, then, researchers may find
themselves
slipping across a line that prohibits treating human subjects
as
means to an end. When that line is crossed, there is very
little
left to protect patients from a callous disregard of their
welfare for the sake of research goals. Even informed
consent,
important though it is, is not protection enough, because of
the
asymmetry in knowledge and authority between researchers and
their subjects. And approval by an institutional review
board,
though also important, is highly variable in its
responsiveness
to patients' interests when they conflict with the
interests of
researchers.
A textbook example of unethical research is
the Tuskegee Study of
Untreated Syphilis. (4) In that study, which was sponsored by the
U.S. Public Health Service and lasted from
1932 to 1972, 412 poor
African-American men with untreated syphilis
were followed and
compared with 204 men free of the disease to determine the
natural history of syphilis. Although there was no very good
treatment available at the time the study began (heavy metals
were the standard treatment), the research continued even
after
penicillin became widely available and was known to be highly
effective against syphilis. The study was not terminated until
it
came to the attention of a reporter and the outrage
provoked by
front-page stories in the Washington Star and New York Times
embarrassed the Nixon administration into calling a halt to it.
(5) The ethical violations were multiple:
Subjects did not
provide informed consent (indeed, they were deliberately
deceived); they were denied the best known treatment; and the
study was continued even after highly effective treatment
became
available. And what were the arguments in favor of the
study? That these poor African-American men probably would
not
have been treated anyway, so the investigators were merely
observing what would have happened if there were no study; and
that the study was important (a "never-to-be-repeated
opportunity," said one physician after penicillin became
available). (6) Ethical concern was even stood on its head when
it was suggested that not only was the information
valuable, but
it was especially so for people like the subjects -- an
impoverished rural population with a very high rate of untreated
syphilis. The only lament seemed to be that many of the
subjects
inadvertently received treatment by other doctors.
Some of these issues are raised by Lurie and Wolfe elsewhere in
this issue of the Journal. They discuss the ethics of
ongoing
trials in the
transmission of human immunodeficiency virus (HIV) infection. (7)
All except one of the trials employ
placebo-treated control
groups, despite the fact that zidovudine
has already been clearly
shown to cut the rate of vertical transmission greatly and
is now
recommended in the
women. The justifications are reminiscent of those for the
antiretroviral treatment anyway, so the investigators are simply
observing what would happen to the subjects' infants if there
were no study. And a placebo-controlled study is the
fastest,
most efficient way to obtain unambiguous information that
will be
of greatest value in the
protests from Wolfe and others to the secretary of Health and
Human Services, the directors of the National
Institutes of
Health (NIH) and
the Centers for Disease Control and Prevention
(CDC) -- the organizations sponsoring the
studies -- argued, "It
is an unfortunate fact that the current standard of perinatal
care for the HIV-infected pregnant women in the sites of
the
studies does not include any HIV prophylactic intervention at
all," and the inclusion of placebo controls
"will result in the
most rapid, accurate, and reliable answer to the question
of the
value of the intervention being studied compared to the
local
standard of care." (8)
Also in this issue of the Journal, Whalen et
al. report the
results of a clinical trial in
prophylaxis against tuberculosis in HIV-infected adults, most of
whom had positive tuberculin skin tests. (9) This study,
too,
employed a placebo-treated control group, and in some ways it
is
analogous to the studies criticized by Lurie
and Wolfe. In the
study, because of long-standing official recommendations
that
HIV-infected persons with positive tuberculin
skin tests receive
prophylaxis against tuberculosis. The first was issued in 1990 by
the CDC's Advisory Committee for Elimination of
Tuberculosis.
(10) It stated that tuberculin-test-positive
persons with HIV
infection "should be considered candidates for preventive
therapy." Three years later, the recommendation was reiterated
more strongly in a joint statement by the American
Thoracic
Society and the CDC, in collaboration with
the Infectious
Diseases Society of
Pediatrics. (11) According to this statement, "... the
identification of persons with dual infection and the
administration of preventive therapy to these persons is of great
importance." However, some believe that these
recommendations
were premature, since they were based largely on the
success of
prophylaxis in HIV-negative persons. (12)
Whether the study by Whalen et al. was
ethical depends, in my
view, entirely on the strength of the preexisting
evidence. Only
if there was genuine doubt about the benefits of
prophylaxis
would a placebo group be ethically justified. This is not
the
place to review the scientific evidence, some of which is
discussed in the editorial of Msamanga
and Fawzi elsewhere in
this issue. (13) Suffice it to say that the case is
debatable.
Msamanga and Fawzi conclude that
"future studies should not
include a placebo group, since preventive therapy should be
considered the standard of care." I agree. The difficult
question
is whether there should have been a placebo group in the
first
place.
Although I believe an argument can be made
that a
placebo-controlled trial was ethically justifiable because it was
still uncertain whether prophylaxis would work, it should
not be
argued that it was ethical because no prophylaxis is the
"local
standard of care" in sub-Saharan
Lurie and Wolfe, that reasoning is badly flawed. (7) As
mentioned
earlier, the Declaration of Helsinki requires control groups
to
receive the "best" current treatment, not the local
one. The
shift in wording between "best" and
"local" may be slight, but
the implications are profound. Acceptance of this ethical
relativism could result in widespread exploitation of vulnerable
carried out in the sponsoring country. (14) Furthermore, it
directly contradicts the Department of Health and Human
Services'
own regulations governing U.S.-sponsored research in
foreign
countries, (15) as well as joint guidelines for research in the
Organizations of Medical Sciences, (16) which
require that human
subjects receive protection at least equivalent to that in the
sponsoring country. The fact that Whalen et al. offered isoniazid
to the placebo group when it was found superior to
placebo
indicates that they were aware of their responsibility to all
the
subjects in the trial.
The Journal has taken the position that it
will not publish
reports of unethical research, regardless of their scientific
merit. (14,17) After deliberating
at length about the study by
Whalen at al., the editors concluded that
publication was
ethically justified, although there remain differences among
us.
The fact that the subjects gave informed
consent and the study
was approved by the institutional review board at the
University
Hospitals of
the Ugandan National AIDS Research Subcommittee certainly
supported our decision but did not allay all our misgivings. It
is still important to determine whether clinical studies
are
consistent with preexisting, widely accepted ethical guidelines,
such as the Declaration of Helsinki, and with federal
regulations, since they cannot be influenced by pressures
specific to a particular study.
Quite apart from the merits of the study by Whalen
et al., there
is a larger issue. There appears to be a general retreat
from the
clear principles enunciated in the Nuremberg Code and the
Declaration of
World. Why is that? Is it because the "local standard
of care" is
different? I don't think so. In my view, that is merely a
self-serving justification after the fact. Is it because diseases
and their treatments are very different in the
that information gained in the industrialized world has no
relevance and we have to start from scratch? That, too, seems
an
unlikely explanation, although here again it is often offered
as
a justification. Sometimes there may be relevant
differences
between populations, but that cannot be assumed. Unless there
are
specific indications to the contrary, the safest and most
reasonable position is that people everywhere are likely to
respond similarly to the same treatment.
I think we have to look elsewhere for the
real reasons. One of
them may be a slavish adherence to the tenets of clinical
trials.
According to these, all trials should be
randomized,
double-blind, and placebo-controlled, if at all possible. That
rigidity may explain the NIH's
pressure on Marc Lallemant to
include a placebo group in his study, as described by Lurie and
Wolfe. (7) Sometimes journals are blamed for
the problem, because
they are thought to demand strict conformity to the
standard
methods. That is not true, at least not at this journal. We
do
not want a scientifically neat study if it is ethically
flawed,
but like Lurie and Wolfe we
believe that in many cases it is
possible, with a little ingenuity, to have both scientific and
ethical rigor.
The retreat from ethical principles may also
be explained by some
of the exigencies of doing clinical research in an
increasingly
regulated and competitive environment. Research in the Third
World looks relatively attractive as it
becomes better funded and
regulations at home become more restrictive. Despite the
existence of codes requiring that human subjects receive at
least
the same protection abroad as at home, they are still
honored
partly in the breach. The fact remains that many studies are
done
in the
sponsoring the work. Clinical trials have become a big business,
with many of the same imperatives. To survive, it is
necessary to
get the work done as quickly as possible, with a minimum
of
obstacles. When these considerations prevail, it seems as if we
have not come very far from
the research community need to redouble our commitment to
the
highest ethical standards, no matter where the research is
conducted, and sponsoring agencies need to enforce those
standards, not undercut them.
Marcia Angell, M.D.
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8. The conduct of clinical trials of
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