Write a 200- to 350- word explanation of the relationship between critical thinking and ethics. See article below.Are the principles and rules of critical thinking applicable to ethical reasoning? Why?If everyone followed the rules and guidelines of logic, would there be a need for ethical decision making? Why? Use examples from the scenarios provided this week to support your answer. Payments will be made if plagiarized.You Decide Ethics of Medical Research.docYou Decide: Ethics of Medical Research
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Pearson MyEthicsKit
You Decide! Ethics of Medical Research
INTRODUCTION
Please read the following materials on this issue by clicking the right arrow button above.
Ethics of Medical Research in Impoverished Countries: Must Medical Research in
Impoverished Countries Follow the Same Procedures as in Wealthy Countries or Can
Different Procedures Be Followed?
The Tuskegee syphilis study, running from 1932 to 1972, was designed to study the course
of untreated syphilis. The research subjects, poor African-American males, were told they
were receiving treatment for their disease; in fact, they received none. The Tuskegee
subjects were not given penicillin, and were actively prevented from obtaining this lifesaving drug; instead, they were monitored as their disease followed its terrible path of
disability, blindness, paralysis, insanity, and death. There is broad agreement that the
Tuskegee study was morally wrong.
There is also now wide agreement about basic principles that must guide legitimate
research with human subjects. Foremost is the requirement of informed consent: Second,
studies must be well designed to yield significant scientific results. Third, subjects must not
be exposed to unnecessary risks or discomfort. Fourth, when a researcher runs a
randomized comparative study between a control group (research subjects who receive
the current standard best treatment, or a placebo, or no treatment) and an experimental
group (subjects who receive the drug or procedure being tested), the researcher must not
have any prior reason to suppose that one group will fare better than the other.
International medical research poses tough ethical issues, particularly when the research
involves North American and European pharmaceutical companies running drug tests
among severely impoverished populations in Africa, Asia, and Latin America. When studies
are done among people with no access to treatment other than through an experimental
drug study, are these subjects giving genuine free consent, or are their desperate
circumstances used to exploit them? Is it legitimate to run drug experiments in
impoverished countries if the price of the tested medication will limit its use to wealthy
nations?
POINT
The Ethics of Medical Research in Impoverished Countries: Researchers Must Follow the
Same Procedures as in Wealthy Countries
ADVOCATE: Marcia Angell, Executive Editor (1988-1999) and Editor-in-Chief (1999-2000)
of New England Journal of Medicine; currently Senior Lecturer in Department of Social
Medicine at Harvard Medical School
SOURCE: “The Ethics of Clinical Research in the Third World,” The New England Journal of
Medicine volume 337, number 12, September 18, 1997: 847-849
An essential ethical condition for a randomized clinical trial comparing two treatments for
disease is that there be no good reason for thinking one is better than the other. 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.
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.
Failure to adhere to this principle in Third World settings is analogous to the failure to
adhere to this principle in the Tuskegee Experiment.
COUNTERPOINT
The Ethics of Medical Research in Impoverished Countries: Researchers Can Use Different
Procedures in Impoverished Countries
ADVOCATE: Salim S. Abdool Karim, Deputy Vice-Chancellor for Research and Development
at the University of Natal in Durban, South Africa; Professor in Clinical Epidemiology at the
Mailman School of Public Health at Columbia University; and Director of the Centre for the
AIDS Program of Research in South Africa
SOURCE: “Placebo Controls in HIV Perinatal Transmission Trials: A South African’s
Viewpoint,” American Journal of Public Health volume 88, number 4, April 1998: 564-566.
Researchers and research agencies from sponsoring countries should not conduct research
in poor countries that would be unethical in their own countries, except under justifiable
extenuating circumstances. At times, such extenuating circumstances exist.
Informed and voluntary participation requires an understanding of the risks and benefits
inherent in the research. In this context, participants should not be exposed to harm or
undue risk, but this can be judged only in relation to a standard. The reality is that
standards-in this case, the standard of care – differ across the world and even within
countries; they are seldom agreed upon internationally.
THE CONTINUING DEBATE
The Continuing Debate: The Question of Abortion
The controversy over wealthy Western pharmaceutical companies carrying out drug
studies in Third World countries continues. The pharmaceutical industry generates
enormous profits, and bringing a new drug to market more quickly can increase profits by
millions or even hundreds of millions of dollars. Studies in impoverished countries can be
done more swiftly, at lower cost, and with less regulation (for example, standards for
informed consent are often lower).
Under The 2000 Declaration of Helsinki, researchers are not allowed to use placebos when
a standard treatment is available, and they must continue treatment of research subjects
(using either the experimental drug or the standard treatment, depending on what proves
best) after the research is completed. Abruptly halting effective treatment at the conclusion
of a study is regarded as cruel and unfair to the research participants. Furthermore, the
Helsinki Declaration requires that all study results be made public. However, compliance
with the Declaration of Helsinki must be voluntary, and the U.S. Food and Drug
Administration has rejected the Declaration, claiming that its requirements are arbitrary
and too demanding.
For a complete reading of this debate, please review the following click here
[Begin Waller_debate10.pdf]
chapter10.qxp 6/28/05 9:09 PM Page 184
Debate 10: THE ETHICS OF MEDICAL RESEARCH IN IMPOVERISHED COUNTRIES
Must Medical Research in Impoverished Countries Follow the Same Procedures as in
Wealthy Countries or Can Different Procedures Be Followed?
RESEARCHERS MUST FOLLOW THE SAME RESEARCH PROCEDURES AS IN WEALTHY
COUNTRIES
ADVOCATE: Marcia Angell, Executive Editor (1988-1999) and Editor-in-Chief (1999-2000)
of New England Journal of Medicine; currently Senior Lecturer in Department of Social
Medicine at Harvard Medical School
SOURCE: “The Ethics of Clinical Research in the Third World,” The New England Journal of
Medicine volume 337, number 12, September 18, 1997: 847-849
RESEARCHERS CAN USE DIFFERENT RESEARCH PROCEDURES IN IMPOVERISHED
COUNTRIES
ADVOCATE: Salim S. Abdool Karim, Deputy Vice-Chancellor for Research and Development
at the University of Natal in Durban, South Africa; Professor in Clinical Epidemiology at the
Mailman School of Public Health at Columbia University; and Director of the Centre for the
AIDS Program of Research in South Africa
SOURCE: “Placebo Controls in HIV Perinatal Transmission Trials: A South African’s
Viewpoint,” American Journal of Public Health volume 88, number 4, April 1998: 564-566.
Medical research has produced wonderful discoveries, but also some ethical horror stories.
The Tuskegee syphilis study, running from 1932 to 1972, was designed to study the course
of untreated syphilis. The research subjects, poor African-American males, were told they
were receiving treatment for their disease; in fact, they received none. Within a few years
after the study was launched, penicillin was recognized as a highly effective treatment for
syphilis. The Tuskegee subjects were not given penicillin, and were actively prevented from
obtaining this life-saving drug; instead, they were monitored as their disease followed its
terrible path of disability, blindness, paralysis, insanity, and death.
There is broad agreement that the Tuskegee study was morally wrong. There is also
now wide agreement about basic principles that must guide legitimate research with
human subjects. Foremost is the requirement of informed consent: Research subjects must
be informed that they are participating in a research project. They cannot, for example, be
given an experimental drug under the guise of treatment. Subjects must be informed of all
risks, and they must freely choose to participate. Second, studies must be well designed to
yield significant scientific results. Third, subjects must not be exposed to unnecessary risks
or discomfort. Fourth—this requirement is somewhat more controversial—when a
researcher runs a randomized comparative study between a control group (research
subjects who receive the current standard best treatment, or a placebo, or no treatment)
and an experimental group (subjects who receive the drug or procedure being tested), the
researcher must not have any prior reason to suppose that one group will fare better than
the other; that is, the two groups must be in a state of equipoise, in which the researcher
honestly does not know which group is likely to benefit more. Furthermore, if there is a
standard effective treatment for the condition being tested, then the control group must
receive that treatment rather than a placebo.
International medical research poses tough ethical issues, particularly when the
research involves North American and European pharmaceutical companies running drug
tests among severely impoverished populations in Africa, Asia, and Latin America. When
studies are done among people with no access to treatment other than through an
experimental drug study, are these subjects giving genuine free consent, or are their
desperate circumstances used to exploit them? Is it legitimate to run drug experiments in
impoverished countries if the price of the tested medication will limit its use to wealthy
nations?
One fiercely debated study—and the focus of the essays by Angell and Karim—
involved the testing of a new treatment procedure to prevent the transmission of HIV from
infected mothers to their newborn children. At the time the studies were done in the late
1990’s, there was a standard treatment process available for preventing maternal HIV
transmission, and it had a success rate of some 70%. It was, however, lengthy, complex, and
expensive. A number of researchers tested programs involving much smaller drug doses
administered more briefly. Studies were conducted among impoverished African women
with almost no access to health care. Also, the control group was given a placebo rather
than the standard effective treatment. Critics of the research argued that the control group
should have been given the standard treatment. Defenders of the research insisted that
while the expensive treatment might be standard in wealthy countries, it certainly was not
the standard in impoverished countries. Some researchers also argued that applying the
equipoise requirement was inappropriate or inapplicable here because the use of a placebo
gave faster and more reliable research results, and thus made a cheaper treatment more
rapidly available.
POINTS TO PONDER
• The policy of The New England Journal of Medicine is not to publish studies that it
regards as ethically flawed. The journal decided to publish the study on HIV
transmission, though with some misgivings. Was that the right decision?
• Angell has been criticized for making a comparison with Tuskegee, on the grounds
that her analogy is too sensational and inaccurate. Is her use of the analogy fair?
• Sa1im Karim argues that local authorities in South Africa approved the research
design. Does that validate the ethical legitimacy of the research?
The Ethics of Medical Research in Impoverished Countries:
Researchers Must Follow the Same Procedures as in Wealthy Countries
MARCIA ANGELL
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. 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 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. It
states, “In research on man [sic], the interest of science and society should never take
precedence over considerations related to the well-being 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. 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 frontpage stories in the Washington Star and New York Times embarrassed the Nixon
administration into calling a halt to it. 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 Tuskegee 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). 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 Third World of regimens to prevent
the vertical transmission of human immunodeficiency virus (HIV) infection. 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 United States for all HIV-infected pregnant women. The justifications
are reminiscent of those for the Tuskegee study: Women in the Third World would not
receive 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 Third World. Thus, in response to 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.”
Also in this issue of the Journal, Whalen et al. report the results of a clinical trial in
Uganda of various regimens of prophylaxis against tuberculosis in HIV-infected adults,
most of whom had positive tuberculin skin tests. 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 United States it would probably be impossible to carry out such a 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. It stated that tuberculintest-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 America and the American Academy of Pediatrics. 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.
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. 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 Africa. For reasons discussed by Lurie and Wolfe, that reasoning is
badly flawed. 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 Third World populations
for research programs that could not be carried out in the sponsoring country.
Furthermore, it directly contradicts the Department of Health and Human Services’ own
regulations governing U.S.-sponsored research in foreign countries, as well as joint
guidelines for research in the Third World issued by WHO and the Council for International
Organizations of Medical Sciences, 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. After deliberating at length about the study by
Whalen et 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
Cleveland and Case Western Reserve University and by 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 Helsinki as applied to research in the Third 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 Third World, so 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. 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 Third
World that simply could not be done in the countries 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 Tuskegee after all.
Those of us in 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.
The Ethics of Medical Research in Impoverished Countries:
Researchers Can Use Different Procedures in Impoverished Countries
SALIM S. ABDOOL KARIM
INTRODUCTION
The scale of the human immunodeficiency virus (HIV) epidemic in South Africa, where
0.76% of pregnant women were HIV infected in 1990 and 14.07% in 1996, highlights the
importance of research to find practical and affordable interventions to curb HIV
transmission. Lurie and Wolfe and Angell have raised the vexed issue under intensive
discussion for some time now in South Africa of whether a placebo arm is ethical in studies
of vertical transmission of HIV.
I agree with Lurie and Wolfe that researchers and research agencies from
sponsoring countries should not conduct research in poor countries that would be
unethical in their own countries, except under justifiable extenuating circumstances.
Indeed, this is also advocated by the Council for International Organizations of Medical
Sciences (CIOMS). However, the situation in South Africa is somewhat different; the funding
sources for ongoing HIV vertical transmission trials, with placebo arms, are local agencies
and the United Nations Program on Acquired Immunodeficiency Syndrome (UNAIDS).
One of the two large HIV perinatal transmission trials currently under way in South
Africa is assessing the effect of vitamin A supplementation; the other trial is a 4-arm trial
assessing a combination of zidovudine and 3TC given for a short period before, during, or
after delivery. The vitamin A study has recruited almost 400 women and is funded by the
South African Department of Health and the South African Medical Research Council. The
short-course combination therapy trial, known as the Petra Study, is a multicenter trial
funded by UNAIDS, and about 400 women will be recruited in each of the 2 sites in South
Africa. Both trials are double-blinded, randomized control trials with placebo arms, and
both have been scrutinized by institutional review boards, known in South Africa as ethics
committees. The vitamin A study was approved by the University of Natal Ethics
Committee, and the Petra study was approved by both the University of Natal and the
University of the Witwatersrand. These studies aim to find an intervention that will be
affordable and implementable in a setting such as South Africa. They are critically
important if the AIDS Clinical Trial Group (ACTG) 076 regimen of zidovudine, which has
been shown to be effective, cannot be implemented.
IS THE ACTG 076 REGIMEN IMPLEMENTABLE IN SOUTH AFRICA?
Although South Africa is a middle income country, cost is a constraint. Program planning
with detailed costing reveals that the ACTG 076 regimen is not affordable without
substantial redirection and reprioritization of health care resources. Currently,
approximately 1.2 million births occur each year in South Africa. Substantial new resources
will be required to test pregnant women with pre- and posttest counseling. Implementing
the ACTG 076 regimen for those identified to be HIV infected will require further resources
to increase the number of clinic visits several fold and to provide the close clinical
management required for patients on antiretroviral drugs. Although the cost of zidovudine
is substantial, important contributors to the costs of implementing the ACTG regimen in
South African are the health service costs. Costs associated with HIV testing and medical
care will be applicable regardless of the therapeutic regimen, but those costs will not be
applicable to an intervention such as vitamin A supplementation, which can be given to all
pregnant women without testing for HIV infection—hence the specific relevance of the
vitamin A trial to the South African situation.
In South Africa, a second constraint to implementation of the ACTG 076 regimen is
the high frequency of home deliveries, particularly in rural communities. A third constraint
is the high frequency of booking for antenatal care appointments that are too late for the
prenatal component of the ACTG 076 regimen, making its widespread use almost
impossible. Additionally, because breast-feeding is common in rural South Africa, HIVpositive women participating in the ACTG 076 regimen will have to be discouraged from
breast-feeding. This could be possible only if breast-milk substitutes are provided either
free or at heavily subsidized prices.
If the ACTG 076 regimen is not being implemented in this country or cannot be
implemented, should it be the standard of care in the control arm of HIV vertical
transmission trials in South Africa? In this commentary, I will consider some of the
scientific and ethical issues in this dilemma.
OTHER TREATMENT OPTIONS FOR THE CONTROL GROUP
Fundamentally, the research question at issue is whether shorter courses of combination
antiretroviral therapy or micronutrient supplementation reduce vertical transmission of
HIV sufficiently to warrant their wide-scale implementation in South Africa. If these
interventions are hypothesized to be as good as or better than ACTG 076, then a control
arm with the ACTG 076 regimen is entirely appropriate. What if the study interventions are
not as good as ACTG 076? This possibility—in stark contrast to the “more optimistic view”
taken by Lurie and Wolfe—must be seriously considered in the design of the trials.
In considering each of the 3 options for the control group in these trials, the real
possibility must be considered that shorter course drug regimens or micronutrient
supplementation may not reduce the HIV vertical transmission rate to the same extent as
the ACTG 076 regimen (e.g., they may be only half as efficacious).
Option 1: No Concurrent Control Group: Historical Data Provide the Comparison
Vertical Transmission Rate
The vertical transmission rate in South Africa has been changing over time. In a cohort of
111 subjects recruited in 1990 through 1991 at King Edward VIII Hospital, the HIV vertical
transmission rate was 27%, while a cohort of 180 subjects recruited at the same hospital in
1993 through 1994 had a rate of 38% (Dr D. Moodley, personal communication). If a
hypothetical nonrandomized study was conducted in 1993 to 1994 with an intervention
that was 33% effective, the outcome would have been an HIV vertical transmission rate of
26%. Without placebo data providing the concurrent rate of 38%, comparing the study rate
of 26% with the rate in 1990 through 1991 of 27% would have led to the conclusion that
the intervention had no effect.
The vertical transmission rate is influenced by many factors, including cesarean
section rates, maternal viral load, and breast-feeding rates. As these factors change over
time, the HIV vertical transmission rate will also change, either increasing or decreasing
depending on which factors change and to what extent. Given the changing HIV vertical
transmission rate, historical comparisons may lead to spurious conclusions and are
therefore not acceptable.
Option 2: A Control Group Using the ACTG 076 Regimen
If a control group uses the ACTG 076 regimen, the clinical trial may be viewed as an
equivalency study. An equivalency study is informative if the study interventions are found
to be as good as, or better than, the control (equivalent) intervention and if the expected
outcome of the control intervention is known. However, the effect of the ACTG 076 regimen
in South Africa is not known, and extrapolation based on data from other settings is fraught
with problems, given differences in breast-feeding rates, sexually transmitted disease rates,
cesarean section rates, levels of viral load, and other variables….
Option 3: A Placebo Control Group
A placebo control group is the only option that would enable the calculation of the absolute
reduction in the HIV vertical transmission rate, regardless of the extent to which it may
differ from the effect of the ACTG 076 regimen. The essential concurrent comparison HIV
vertical transmission rate is available. A meaningful result would be obtained even if the
effect of the study interventions were lower than that of the ACTG 076 regimen. It would be
possible to calculate whether the study interventions make any difference at all and, if so,
to what extent they lower the HIV vertical transmission rate. Therefore, on scientific
grounds, a placebo control group is essential.
IS A PLACEBO CONTROL GROUP ETHICALLY JUSTIFIABLE?
The starting point for all clinical trials is the assurance that trial participants will be
protected from exploitation. Persons who are being recruited into a research project must
be allowed to exercise their own judgment freely (autonomy) in deciding whether or not to
participate in the research. Ethics committees in South Africa have a strong tradition of
vigorously upholding this principle. Legally, the South African Medical Research Council
has an obligation to protect and uphold the ethical standards of research in South Africa.
Guidelines from the Council for International Organizations of Medical Sciences are
extensively applied and the Medical Research Council’s guidelines have been widely
adopted in South Africa. Although institutional review has been undertaken for all the HIV
perinatal transmission trials in South Africa, further steps to monitor the ethical standards
of informed consent have also been voluntarily pursued by some of the research groups.
Informed and voluntary participation requires an understanding of the risks and
benefits inherent in the research. In this context, participants should not be exposed to
harm or undue risk, but this can be judged only in relation to a standard. The reality is that
standards—in this case, the standard of care—differ across the world and even within
countries; they are seldom agreed upon internationally. Although the ACTG 076 regimen of
therapy is the standard of care in some countries, it is not an international standard, such
as is set by the World Health Organization. Providing high-quality routine care to the
control arm without providing the ACTG 076 regimen of zidovudine cannot then be
construed as causing undue risk or harm to the study participants. No therapy that they
may otherwise receive is being withheld from study participants. To extend this argument,
if the control arm has to be afforded an external standard of care that can produce a
substantial reduction in the HIV vertical transmission rate, it then cannot be justified for
participants to be randomized in a study intervention arm if there is a reasonable chance
that the interventions under study are not as good as the ACTG 076 regimen. It is,
therefore, my opinion that the placebo control arm is ethically justifiable.
Standards of care evolve, and the acceptable standards of care will change over time.
This does not mean that ethics are flexible; the consistent application of the basic principles
of ethics in a world that varies markedly and changes rapidly is not inconsistent with
differing standards of care being ethically acceptable in different settings or at different
times.
CONCLUSION
Everyone agrees that there is an urgent need to reduce vertical transmission of HIV, and
this remains the central goal of the studies in South Africa. The local imperative is to
develop and demonstrate further the efficacy of an affordable and implementable
intervention to reduce HIV vertical transmission. While such an intervention need not be as
good as the ACTG 076 regimen of therapy, its impact on HIV vertical transmission must be
known, because this information will be the basis of policy that will aim to protect
hundreds of thousands of infants from becoming infected with HIV.
THE CONTINUING DEBATE:
The Ethics of Medical Research in Impoverished Countries
What Is New
The controversy over wealthy Western pharmaceutical companies carrying out drug
studies in Third World countries continues. The pharmaceutical industry generates
enormous profits, and bringing a new drug to market more quickly can increase profits by
millions or even hundreds of millions of dollars. Studies in impoverished countries can be
done more swiftly, at lower cost, and with less regulation (for example, standards for
informed consent are often lower).
Under The 2000 Declaration of Helsinki, researchers are not allowed to use placebos
when a standard treatment is available, and they must continue treatment of research
subjects (using either the experimental drug or the standard treatment, depending on what
proves best) after the research is completed. Abruptly halting effective treatment at the
conclusion of a study is regarded as cruel and unfair to the research participants.
Furthermore, the Helsinki Declaration requires that all study results be made public.
However, compliance with the Declaration of Helsinki must be voluntary, and the U.S. Food
and Drug Administration has rejected the Declaration, claiming that its requirements are
arbitrary and too demanding.
Where to Find More
For a very readable but deeply disturbing account of the Tuskegee experiment, see James
H. Jones, Bad Blood: The Tuskegee Syphilis Experiment (New York: The Free Press, 1981,
1993). An excellent collection of articles on the experiment is by Susan M. Reverby, editor,
Tuskegee’s Truths: Rethinking the Tuskegee Syphilis Study (Chapel Hill: University of North
Carolina Press, 2000).
Baruch A. Brody, The Ethics of Biomedical Research: An International Perspective
(New York: Oxford University Press, 1998) examines a wide range of research-related
issues. Ruth Macklin, Double Standards in Medical Research in Developing Countries
(Cambridge: Cambridge University Press, 2004), is a remarkably good book, covering all
the major issues and providing a superb guide to the current literature. See also two
excellent articles by Macklin: “After Helsinki: Unresolved Issues in International Research,”
Kennedy Institute of Ethics Journal Volume 11, number 1, 2001: 17–36; and “International
Research: Ethical Imperialism or Ethical Pluralism,” Accountability in Research volume 7,
2001: 5 9–83. A clear introduction, with special emphasis on the positions taken by major
oversight and regulatory bodies, is Aurora Plomer, The Law and Ethics of Medical Research:
International Biolethics and Human Rights (London: Cavendish Publishing, 2005).
The article that prompted much of the international drug testing debate is Peter
Lurie and Sidney M. Wolfe, “Unethical Trials of Interventions to Reduce Perinatal
Transmission of the Human Immunodeficiency Virus in Developing Countries,” New
England Journal of Medicine volume 337, September 18, 1997: 853–856. Critical of that
article is Robert A Crouch and John D. Arras, “AZT Trials and Tribulations,” Hastings Center
Report volume 28, number 6, 1998: 26–34; that issue of Hastings Center Report contains a
number of other articles on the dispute. See also Bioethics volume 12, number 4, October
1998, which focuses on that question. Alex John London, “Equipoise and International
Human-Subjects Research,” Bioethics volume 15, number 4, 2001, discusses the equipoise
requirement in the context of international research. Three years after publishing the Lurie
and Wolfe article and her own editorial on the subject, Marcia Angeli wrote an excellent
follow-up to the continuing debate: “Investigators’ Responsibilities for Human Subjects in
Developing Countries,” New England Journal of Medicine volume 342, Number 13, March
30, 2000: 967–968. American Journal of Public Health volume 88, number 4, April 1998
contains excellent articles devoted to the controversy. Karin B. Michels and Kenneth J.
Rothrnan, “Update on Unethical Use of Placebos in Randomized Trials,” Bioethics, Volume
17, Number 2, 2003: 188–204, argue against the continued practice of using placebo
studies in Third World research. An excellent critique of the arguments in favor of relaxed
research standards in Third World countries is offered by M. H. Kottow, “Who is my
Brother’s Keeper?” Journal of Medical Ethics, volume 28, 2002: 24–27.
D. R. Cooley, “Distributive Justice and Clinical Trials in the Third World,” Theoretical
Medicine, volume 22, 2001: 151–167, argues that researchers are under no obligation to
guarantee that drugs successfully tested in third world countries will ultimately be
available to those who live there. Solomon R. Benatar, “Distributive Justice and Clinical
Trials in the Third World,” Theoretical Medicine, volume 22, 2001: 169–176, insists that
basic principles of distributive justice require strong efforts to improve health care in the
impoverished host countries.
[End Waller_debate10.pdf]
WATCH
Watch More On This Issue
Now that you’ve read about this issue, please watch the following video(s) from ABC NEWS
for more relevant information on this issue.
Aids in Africa
[Begin Aids in Africa]
[on-screen text: Nightline: July 8, 2003]
The nation of Uganda sits virtually in the center of sub-Saharan Africa; it has endured the
brutal dictatorship of Idi Amin, and years of civil war. Yet now it fights perhaps its most
important battle: the one against AIDS. And as ABC’s David Wright now reports, despite the
horrible odds, Uganda appears to be winning.
[singing]
At a daycare center in Kampala, the children rehearse for a concert; the President of the
United States is coming, and they’ve been asked to sing. All of these kids have full-blown
AIDS; most have less than a year to live, some are just skin and bones. The U.N. estimates
there are nearly 3 million children living with HIV/AIDS in Africa, 110,000 in Uganda alone.
These are the lucky ones. At Jaja’s Home they receive food, medicine, and love, but the
teachers all know they will outlive every one of their charges. What’s her name?
She’s called Sonia.
Sonia is fifteen months old. Both her parents are already dead. How do you keep from
crying?
Of course you can’t avoid the emotions, but you learn to live with them. You know that
what you’re doing is making a difference in a child’s life for a period of time.
Compassion borne of grim familiarity: Ask anyone in Uganda if they’ve lost a family
member to the disease, and they’ll usually name three or four. That is why President
Yoweri Museveni long ago made beating the disease not just a priority, but a national
crusade.
Our President, who was willing to come out at that time when AIDS was a disease of shame,
a disease that would drive away investors and tourists. Instead of sweeping the dust under
the carpet, which you could have chosen to do, like many of our neighboring countries in
Africa did, he came out bold and said, “Hey, we have this problem.”
Uganda makes sure everyone knows how to protect themselves. Here, frankness is the
most important weapon against the spread of the disease, but illiteracy is high, so they use
songs. Every member of this chorus is HIV positive; they’re sharing their experiences as a
warning to others. The audience, a group of traditional healers who are often the primary
caregivers for people infected. A decade ago, this used to be a public park; now, it is a
shantytown shopping mall of herbal remedies.
This one is for all symptoms of AIDS.
Dr. B. K. Massey makes all the medicine he sells, using his own secret recipe.
This is for two weeks.
As he dispenses his herbal medication, he also dispenses advice.
If I don’t know anything about AIDS, you will teach me about AIDS. If someone doesn’t
know about AIDS, someone will teach him.
Uganda also relies on more modern medicine. Anti-retroviral drugs are widely available to
those who can afford them. HIV testing is required of pregnant women, and is available at
reduced cost to everyone.
So you just ring, make an appointment, and we wait for you.
Any day of the week.
Any day of the week, even on a Sunday, even on a public holiday.
Uganda has also been at the forefront of the international effort to find a vaccine against
AIDS. Four years ago, this lab was the site of the first AIDS vaccine trials in Africa; earlier
this year, human trials began on two new vaccines. Uganda’s all-out war against AIDS has
shown dramatic results: A decade ago, the U.N. estimated that 1 in 5 people here were
living with AIDS; today, the estimate is 1 in 20. Of course, there’s also a grim side to those
statistics, because it means so many people who were living with the virus have died.
Naseem Umatum has buried nine children and six grandchildren; half of the fifteen
surviving grandchildren are sick. She’s 70 years old. She should be cared for; she should not
have to care for so many.
[translated] That’s true, she says, but all my children have died.
There are believed to be 13 million AIDS orphans in sub-Saharan Africa, but Uganda has
more than any other country: nearly 2 million of them. These boys have no one but the
neighbors to look after them. This spring, their mother became so ill, she went away; she
died a month ago. They are still waiting for her to come home. AIDS may be on the
defensive here, but the disease is still winning. At Jaja’s Home, the end of the school day
brings a heartbreaking ritual. As loving and as caring an environment as this place clearly
is, one cannot help but watch this and think of the day not long from now when all these
children will be gone for good. This is David Wright for Nightline in Kampala, Uganda.
[End Aids in Africa]
SURVEY
What Would You Do?
Now that you have read about the various positions on this issue and have seen a video,
please click here to give us your opinion on this issue.
[begin PearsonSurvey.html]
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[end clip]
[end PearsonSurvey.html]
DECIDE
What Do You Know?
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close out of this simulation and return to your course to answer some questions on this
issue.

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