The
Number 12
[SOUNDING BOARD]
Unethical Trials of Interventions to
Reduce Perinatal Transmission of the
Human Immunodeficiency Virus in
Developing Countries
Defining Placebo as the Standard of
Care in Developing Countries
Some officials and researchers have
defended the use of
placebo-controlled studies in developing countries by arguing
that the subjects are treated at least according
to the standard
of care in these countries, which consists of
unproven regimens
or no treatment at all. This assertion reveals
a fundamental
misunderstanding of the concept of the standard of care. In
developing countries, the standard of care (in this
case, not
providing zidovudine to HIV-positive
pregnant women) is not based
on a consideration of alternative treatments or
previous clinical
data, but is instead an economically determined
policy of
governments that cannot afford the prices set by drug
companies.
We agree with the Council for
International Organizations of
Medical Sciences that researchers
working in developing countries
have an ethical responsibility to provide
treatment that conforms
to the standard of care in the sponsoring
country, when possible.
(9) An exception would be a standard
of care that required an
exorbitant expenditure, such as the cost of building a
coronary
care unit. Since zidovudine
is usually made available free of
charge by the manufacturer for use in clinical
trials, excessive
cost is not a factor in this case. Acceptance of
a standard of
care that does not conform to the standard in the
sponsoring
country results in a double standard in research.
Such a double
standard, which permits research designs that are
unacceptable in
the sponsoring country, creates an incentive to
use as research
subjects those with the least access to health care.
What are the potential implications
of accepting such a double
standard? Researchers might inject live malaria
parasites into
HIV-positive subjects in
the progression of HIV infection, even though
the study protocol
had been rejected in the
might randomly assign malnourished San (bushmen)
to receive
vitamin-fortified or standard bread. One might also justify
trials of HIV vaccines in which the subjects were
not provided
with condoms or state-of-the-art counseling about
safe sex by
arguing that they are not customarily provided in
the developing
countries in question. These are not simply
hypothetical
worst-case scenarios; the first two studies have
already been
performed, (22,23) and the third has been proposed and
criticized. (24)
Annas and Grodin
recently commented on the characterization and
justification of placebos as a standard of care:
"'Nothing' is a
description of what happens; 'standard of care' is a
normative
standard of effective medical treatment, whether or
not it is
provided to a particular community." (25)
References
1. Connor EM, Sperling RS, Gelber R, et al. Reduction of
maternal-infant transmission of human
immunodeficiency virus type
1
with zidovudine treatment. N Engl
J Med 1994;331:1173-80.
Return to:
Introduction
2. Sperling RS,
load, zidovudine
treatment, and the risk of transmission of human
immunodeficiency virus type 1 from mother to
infant.
1996;335:1621-9.
Return to:
Introduction
3. Recommendations
of the
on the use of zidovudine to reduce perinatal
transmission of
human immunodeficiency virus. MMWR Morb Mortal Wkly Rep
1994;43(RR-11):1-20.
Return to:
Introduction
4. Fiscus SA, Adimora AA, Schoenbach VJ, et al. Perinatal HIV
infection and the effect of zidovudine therapy on transmission in
rural and urban counties. JAMA 1996;275:1483-8.
Return to:
Introduction
5. Cooper E, Diaz
C, Pitt J, et al. Impact of ACTG 076: use of
zidovudine during pregnancy and
changes in the rate of HIV
vertical transmission. In: Program
and abstracts of the Third
Conference on
Retroviruses and Opportunistic Infections,
Infectious Diseases
Society of
Return to:
Introduction
6. Simonds RJ, Nesheim S, Matheson
P, et al. Declining mother to
child HIV transmission following perinatal ZDV recommendations.
Presented at the
11th International Conference on AIDS,
Return to:
Introduction
7. Scarlatti G. Paediatric HIV infection. Lancet 1996;348:863-8.
Return to:
Introduction
8. Recommendations
from the meeting on mother-to-infant
transmission of HIV by use of antiretrovirals,
Health
Organization,
Return to:
Introduction
9. World Health
Organization. International ethical guidelines
for biomedical research
involving human subjects.
for International Organizations
of Medical Sciences, 1993.
Return to:
Introduction | Defining Placebo as the Standard of
Care in Developing
Countries
10. 45 CFR 46.111(a)(1).
Return to:
Introduction
11. Testing
equivalence of two binomial proportions. In: Machin
D,
Campbell MJ. Statistical tables for the design of
clinical
trials.
Return to:
Introduction | Justifying Placebo-Controlled Trials by
Claiming They Are
More Rapid
12. Brennan TA.
Letter to Gilbert Meier, NIH Division of Research
Ethics,
Return to:
Introduction
13. Lallemant M, Vithayasai V. A
short ZDV course to prevent
perinatal HIV in
Health,
Return to: Asking
the Wrong Research Question
14. Varmus H. Testimony before the Subcommittee on Human
Resources,
Committee on Government Reform and
House of
Representatives,
Return to: Asking
the Wrong Research Question
15. Draft talking
points: responding to Public Citizen press
conference. Press release of the
National Institutes of Health,
Return to:
Inadequate Analysis of Data from ACTG 076 and Other
Sources
16. Questions and
answers: CDC studies of AZT to prevent
mother-to-child HIV transmission in
developing countries. Press
release of the Centers for Disease
Control and Prevention,
Return to:
Inadequate Analysis of Data from ACTG 076 and Other
Sources
17. Questions and
answers on the UNAIDS sponsored trials for the
prevention of mother-to-child
transmission: background brief to
assist in responding to issues
raised by the public and the
media. Press release
of the United Nations AIDS Program. (undated
document.)
Return to:
Inadequate Analysis of Data from ACTG 076 and Other
Sources
18. Halsey NA, Meinert CL, Ruff AJ, et al.
Letter to Harold
Varmus, Director of National
Institutes of Health.
Return to:
Inadequate Analysis of Data from ACTG 076 and Other
Sources
19. Wiktor SZ, Ehounou
E. A randomized placebo-controlled
intervention study to evaluate the
safety and effectiveness of
oral zidovudine
administered in late pregnancy to reduce the
incidence of mother-to-child
transmission of HIV-1 in
Prevention. (undated
document.)
Return to:
Inadequate Analysis of Data from ACTG 076 and Other
Sources
20. Rouzioux C, Costagliola D, Burgard M, et al. Timing of
mother-to-child HIV-1 transmission depends
on maternal status.
AIDS 1993;7:Suppl 2:S49-S52.
Return to:
Inadequate Analysis of Data from ACTG 076 and Other
Sources
21. Freedman B.
Equipoise and the ethics of clinical research. N
Engl J Med 1987;317:141-5.
Return to:
Inadequate Analysis of Data from ACTG 076 and Other
Sources
22. Heimlich HJ, Chen XP, Xiao BQ, et al. CD4
response in
HIV-positive
patients treated with malaria therapy. Presented at
the 11th International
Conference on AIDS,
7-12,
1996. abstract.
Return to: Defining
Placebo as the Standard of Care in Developing
Countries
23. Bishop WB, Laubscher I, Labadarios D, Rehder P, Louw ME,
Fellingham SA. Effect of vitamin-enriched
bread on the vitamin
status of an isolated rural
community -- a controlled clinical
trial.
Return to: Defining
Placebo as the Standard of Care in Developing
Countries
24. Lurie P, Bishaw M, Chesney MA, et al. Ethical, behavioral,
and social aspects of HIV
vaccine trials in developing countries.
JAMA 1994;271:295-301.
Return to: Defining
Placebo as the Standard of Care in Developing
Countries
25. Annas G, Grodin M. An apology is
not enough.
Return to: Defining
Placebo as the Standard of Care in Developing
Countries
26. Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical
research. I. Empirical and
methodological myths. J Law Med Ethics
1996;24:243-51.
Return to:
Justifying Placebo-Controlled Trials by Claiming They
Are More Rapid
27. Varmus H. Comments at the meeting of the Advisory Committee
to the Director of the
National Institutes of Health, December
12,
1996.
Return to: Toward a
Single International Standard of Ethical
Research
28. Angell M. Ethical imperialism? Ethics in international
collaborative clinical research. N Engl J Med 1988;319:1081-3.
Return to: Toward a
Single International Standard of Ethical
Research
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