The
Number 14
SOUNDING BOARD
Ethical Complexities of Conducting Research
in Developing Countries
One of the great challenges in medical
research is to conduct
clinical trials in developing countries that will lead to
therapies that benefit the citizens of these countries.
Features
of many developing countries -- poverty, endemic
diseases, and a
low level of investment in health care systems -- affect
both the
ease of performing trials and the selection of trials that
can
benefit the populations of the countries. Trials that make
use of
impoverished populations to test drugs for use solely in
developed countries violate our most basic understanding of
ethical behavior. Trials that apply scientific knowledge to
interventions that can be used to benefit such populations are
appropriate but present their own ethical challenges. How do we
balance the ethical premises on which our work is based with
the
calls for public health partnerships from our colleagues in
developing countries?
Some commentators have been critical of
research performed in
developing countries that might not be found ethically
acceptable
in developed countries. Specifically, questions have
been raised
about trials of interventions to prevent maternal-infant
transmission of the human immunodeficiency virus (HIV) that have
been sponsored by the National Institutes of Health (NIH) and the
Centers for Disease Control
and Prevention (CDC). (1,2) Although
these commentators raise important issues, they have not
adequately considered the purpose and complexity of such trials
and the needs of the countries involved. They also allude
inappropriately to the infamous
test an intervention. The
people of a known, effective, affordable intervention. To
claim
that countries seeking help in stemming the tide of
maternal-infant HIV transmission by seeking usable interventions
have followed that path trivializes the suffering of the
men in
the
today's trials.
After the
national commission was established to develop principles and
guidelines for the protection of research subjects. The new
system of protection was described in the
Although largely compatible with the World
Medical Association's
Declaration of
principles: respect for persons (the recognition of the right of
persons to exercise autonomy), beneficence (the minimization
of
risk incurred by research subjects and the maximization of
benefits to them and to others), and justice (the principle
that
therapeutic investigations should not unduly involve persons from
groups unlikely to benefit from subsequent applications of
the
research).
There is an inherent tension among these
three principles. Over
the years, we have seen the focus of debate shift from
concern
about the burdens of participation in research
(beneficence) to
equitable access to clinical trials (justice). Furthermore, the
right to exercise autonomy was not always fully available
to
women, who were excluded from participating in clinical
trials
perceived as jeopardizing their safety; their exclusion clearly
limited their ability to benefit from the research. Similarly,
persons in developing countries deserve research that
addresses
their needs.
How should these principles
be applied to research conducted in
developing countries? How can we -- and they -- weigh the
benefits and risks? Such research must be developed in concert
with the developing countries in which it will be
conducted. In
the case of the NIH and CDC
trials, there has been strong and
consistent support and involvement of the scientific and public
health communities in the host countries, with local as well
as
United States-based scientific and ethical
reviews and the same
requirements for informed consent that would exist if the work
were performed in the
partnership. Interventions that could be expected to be made
available in the
resources of a developing country or exceed the capacity of its
health care infrastructure. Might we support a trial in another
country that would not be offered in the
because the burden of disease might make such a study more
compelling in that country. Even if there were some risks
associated with intervention, such a trial might pass the test
of
beneficence. Might we elect not to support a trial of an
intervention that was beyond the reach of the citizens of the
other country? Yes, because that trial would not pass the
test of
justice.
Trials supported by the NIH
and the CDC, which are designed to
reduce the transmission of HIV from mothers to infants in
developing countries, have been held up by some observers as
examples of trials that do not meet ethical standards. We
disagree. The debate does not hinge on informed consent, which
all the trials have obtained. It hinges instead on
whether it is
ethical to test interventions against a placebo control when
an
effective intervention is in use elsewhere in the world. A
background paper sets forth our views on this matter more fully.
(5) The paper is also available on the World
Wide Web (at
http://www.nih.gov/news/mathiv/mathiv.htm).
One such effective intervention -- known as
AIDS Clinical Trials
Group protocol 076 -- was a major
breakthrough in the search for
a way to interrupt the transmission of HIV from mother
to infant.
The regimen tested in the original study,
however, was quite
intensive for pregnant women and the health care system.
Although
this regimen has been proved effective, it requires that
women
undergo HIV testing and receive counseling about their HIV
status
early in pregnancy, comply with a lengthy oral regimen and
with
intravenous administration of the relatively expensive
antiretroviral drug zidovudine, and
refrain from breast-feeding.
In addition, the newborn infants must receive
six weeks of oral
zidovudine, and both mothers and infants must be carefully
monitored for adverse effects of the drug. Unfortunately, the
burden of maternal-infant transmission of HIV is greatest in
countries where women present late for prenatal care, have
limited access to HIV testing and counseling, typically
deliver
their infants in settings not conducive to intravenous drug
administration, and depend on breast-feeding to protect their
babies from many diseases, only one of which is HIV
infection.
Furthermore, zidovudine
is a powerful drug, and its safety in the
populations of developing countries, where the incidences of
other diseases, anemia, and malnutrition are higher than in
developed countries, is unknown. Therefore, even though the 076
protocol has been shown to be effective in some countries, it
is
unlikely that it can be successfully exported to many others.
In addition to these hurdles, the wholesale
cost of zidovudine in
the 076 protocol is estimated to be in excess of $800 per
mother
and infant, an amount far greater than most developing
countries
can afford to pay for standard care. For example, in
cost of zidovudine alone for the
076 regimen for one HIV-infected
woman and her child is more than 600 times the annual per
capita
allocation for health care.
Various representatives of the ministries of
health, communities,
and scientists in developing countries have joined with
other
scientists to call for less complex and less expensive
interventions to counteract the staggering impact of
maternal-infant transmission of HIV in the developing world. The
World Health Organization moved promptly
after the release of the
results of the 076 protocol, convening a panel of researchers
and
public health practitioners from around the world. This panel
recommended the use of the 076 regimen throughout the
industrialized world, where it is feasible, but also called for
studies of alternative regimens that could be used in
developing
countries, observing that the logistical issues and costs
precluded the widespread application of the 076 regimen. (6) To
this end, the World Health Organization asked UNAIDS, the Joint
United Nations Programme
on HIV/AIDS, to coordinate international
research efforts to develop simpler, less costly
interventions.
The scientific community is responding by
carrying out trials of
several promising regimens that developing countries
recognize as
candidates for widespread delivery. However, these trials are
being criticized by some people because of the use of
placebo
controls. Why not test these new interventions against the 076
regimen? Why not test them against other interventions that
might
offer some benefit? These questions were carefully
considered in
the development of these research projects and in their
scientific and ethical review.
An obvious response to the ethical objection
to
placebo-controlled trials in countries where there is no current
intervention is that the assignment to a placebo group does not
carry a risk beyond that associated with standard practice,
but
this response is too simple. An additional response is
that a
placebo-controlled study usually provides a faster answer with
fewer subjects, but the same result might be achieved with
more
sites or more aggressive enrollment. The most compelling
reason
to use a placebo-controlled study is that it provides
definitive
answers to questions about the safety and value of an
intervention in the setting in which the study is performed, and
these answers are the point of the research. Without clear
and
firm answers to whether and, if so, how well an
intervention
works, it is impossible for a country to make a sound
judgment
about the appropriateness and financial feasibility of
providing
the intervention.
For example, testing two or more
interventions of unknown benefit
(as some people have
suggested) will not necessarily reveal
whether either is better than nothing. Even if one surpasses
the
other, it may be difficult to judge the extent of the
benefit
conferred, since the interventions may differ markedly in other
ways -- for example, cost or toxicity. A
placebo-controlled study
would supply that answer. Similarly, comparing an
intervention of
unknown benefit -- especially one that is affordable in a
developing country -- with the only intervention with a known
benefit (the 076 regimen) may provide information that is not
useful for patients. If the affordable intervention is less
effective than the 076 regimen -- not an unlikely outcome --
this
information will be of little use in a country where the more
effective regimen is unavailable. Equally important, it will
still be unclear whether the affordable intervention is
better
than nothing and worth the investment of scarce health
care
dollars. Such studies would fail to meet the goal of
determining
whether a treatment that could be implemented is worth
implementing.
A placebo-controlled trial is not the only
way to study a new
intervention, but as compared with other approaches, it offers
more definitive answers and a clearer view of side
effects. This
is not a case of treating research subjects as a means
to an end,
nor does it reflect "a callous disregard of their
welfare." (2)
Instead, a placebo-controlled trial may be
the only way to obtain
an answer that is ultimately useful to people in similar
circumstances. If we enroll subjects in a study that exposes them
to unknown risks and is designed in a way that is
unlikely to
provide results that are useful to the subjects or others in
the
population, we have failed the test of beneficence.
Finally, the NIH-
and CDC-supported trials have undergone a
rigorous process of ethical review, including not only the
participation of the public health and scientific communities in
the developing countries where the trials are being
performed but
also the application of the
human research subjects by relevant institutional review
boards
in the
from local governments has been obtained, and each active
study
has been and will continue to be reviewed by an
independent data
and safety monitoring board.
To restate our main points: these studies
address an urgent need
in the countries in which they are being conducted and
have been
developed with extensive in-country participation. The studies
are being conducted according to widely accepted
principles and
guidelines in bioethics. And our decisions to support these
trials rest heavily on local support and approval. In a
letter to
the NIH dated
Research Committee of the Uganda Cancer
Institute, wrote:
These are Ugandan studies conducted by
Ugandan investigators
on Ugandans. Due to lack of resources we have been
sponsored
by organizations like yours. We are grateful that you
have
been able to do so.... There is a mix up of issues here
which needs to be clarified. It is not NIH
conducting the
studies in
their people for the good of their people.
The scientific and ethical issues concerning
studies in
developing countries are complex. It is a healthy sign that we
are debating these issues so that we can continue to
advance our
knowledge and our practice. However, it is essential that the
debate take place with a full understanding of the nature of
the
science, the interventions in question, and the local factors
that impede or support research and its benefits.
Harold Varmus, M.D.
National Institutes of Health
David Satcher,
M.D., Ph.D.
Centers for Disease Control and Prevention
Editor's note Letters on this subject will be
published in a
subsequent issue of the Journal, along with the responses of Dr.
Angell and Drs. Lurie
and Wolfe.
References
1. Lurie P, Wolfe
SM. Unethical trials of interventions to reduce
perinatal transmission of the human immunodeficiency virus in
developing countries. N Engl J Med
1997;337:853-6.
Return to: Text
2. Angell M. The ethics of clinical research in the third world.
N Engl J Med 1997;337:847-9.
Return to: Text
3. National Commission for the Protection of
Human Subjects of
Biomedical and Behavioral
Research.
principles and guidelines for the protection of human subjects
of
research.
(GPO 887-809.)
Return to: Text
4. World Medical Association Declaration of
the 18th World Medical Assembly,
the 48th World Medical Assembly,
Return to: Text
5. The conduct of clinical trials of
maternal-infant transmission
of HIV supported by the United States Department of
Health and
Human Services in
developing countries.
Department of Health and Human Services, July
1997.
Return to: Text
6. Recommendations from the meeting on
mother-to-infant
transmission of HIV by use of antiretrovirals,
Health Organization,
Copyright © 1997 by the