THE MONDAY REVIEW (May 11, 1998 - Issue #2)

15. HIV, AZT, AND THE ETHICS OF THIRD WORLD CLINICAL TRIALS
Deborah Hellman (University of Maryland) presents a short review
of a medical research ethics problem that first came to public
attention last year. We have attached a series of reports that
appeared during the past year in SCIENCE-WEEK to give a fuller
account, but here is the essence of Hellman's piece: "The CDS (US
Centers for Disease Control) and the National Institutes of
Health (US) chose to compare the short-course therapies with
placebos. This method promised to show clearly and indisputably
whether the new treatment was better than nothing and by how
much. But it also meant handing out a useless pill for a fatal
disease even though researchers already had a drug they believed
would work." The blurb for the Hellman article states: "Eighteen
babies who could probably have been saved recently contracted HIV
from their mothers as part of a test of a cheaper AIDS prevention
treatment that might save thousands of lives. Was it worth it?"
(The New Republic 27 Apr 98) (The Monday Review 11 May 98)
-------------------
Related Background:
ETHICS OF PLACEBO-CONTROLLED 3RD WORLD STUDIES REVISITED
The New England Journal of Medicine has now published a
collection of 19 letters from 41 researchers and clinicians in 7
countries concerning the journal's condemnation last year of
placebo-controlled trials in underdeveloped countries of a drug
(zidovudine) to prevent transmission of HIV from pregnant women
to their fetuses, and of another study involving placebo-
controlled trials of preventive therapy for tuberculosis in HIV-
infected people in Uganda. The US National Institutes of Health
and the US Centers for Disease Control were and/or are intimately
involved in these studies, but the heads of these two federal
agencies (H. Varmus and D. Satcher) apparently declined to
respond to any of the letters directly addressing their public
statements. This is a complex subject that cannot be done justice
in a few lines, but the problems addressed by people on all sides
of these issues are of extreme importance to the current and
future development of international medical research ethics, and
this collections of letters in the NEJM will be a classic
collection for a long time to come.
(New England J. Med. 19 Mar 98)
-------------------
Related Background:
HIV TRIALS CONTROVERSY AND TRANSMISSION IN PREGNANT WOMEN
We have had a number of reports in this publication about a
controversy concerning ethical aspects of anti-HIV drug trials in
undeveloped countries, the controversy, in brief, focusing on the
use of placebos when the placebo groups might benefit consider-
ably from the test drug, and when such research placebo protocols
in drug trials involving a drug known to be efficacious are not
allowed in the industrialized nations. Now a US-funded drug trial
in Thailand, designed to test the drug AZT in pregnant women as
an agent against transmission of HIV from the women to their
newborn children, has been halted early and declared to demonstr-
ate that administration of AZT during the final weeks of preg-
nancy does indeed reduce the transmission of HIV to newborn
children by 50%. The drug was already known to do this in con-
junction with other drugs in an expensive regimen, but this trial
was designed to determine if AZT is useful alone in an inexpens-
ive regimen as opposed to a placebo. Those who support such
placebo trials say the speedy conclusion of the research was
facilitated by the placebo controls, while those who oppose such
research continue to argue that the use of placebos in this
instance was unnecessary and unethical, and that data comparable
to the Thailand trial have been available since 1994.
QY: Eliot Marshall <science_editors@aaas.org> (Science 27 Feb 98)
-------------------
Related Background:
A PROBLEMATIC DOUBLE STANDARD IN BIOETHICS
During the past year, a schism of sorts has developed among
bioethicists and people concerned with bioethics. The particular
focus has been the protocols of AIDS research in so-called
developing countries, but the issue concerns more than AIDS, and
indeed pertains to any clinical research involving human subjects
in such regions. The problem is essentially as follows: Consider
two countries A and B. A is rich and B is poor, and in both
countries, the same serious lethal disease is rampant. A drug
treatment exists, affordable by the government of the rich
country but not affordable by the government of poor country. In
the rich country, research guidelines prohibit protocols that
involve withholding drug treatment from patients diagnosed with
the disease; in the poor country, since the drug is unavailable,
no such guidelines exist. Some clinical researchers in the poor
country wish to focus on assessment of locally available
treatment methods, particularly preventive methods involving
vaccines, but the country is too poor for these research efforts.
The rich country is also interested in vaccine research, but such
research is now difficult to do in the rich country because the
ethical requirements of drug treatment in the rich country have
"contaminated" the patient population so that it is difficult if
not impossible to assess the effectiveness of a vaccine. Research
teams from the rich country therefore collaborate with research
teams in the poor country to carry out the relevant vaccine
research in the poor country, the protocol involving the
withholding of the life-saving drug treatment from the control
patient group with the rationalization that the drug is not
available in the poor country anyway. Such, it appears, is the
ethical problem now facing the international medical research
community. Are clinical researchers to do their research with
human patients with two standards of ethics, one standard for
rich countries and another standard for poor countries? One has
the feeling this is one of those questions whose answer one way
or the other will be a defining moment in the history of bio-
ethics. In a family, if one member is ill, the members of the
family usually pool resources. The same occurs in a group, a
tribe, or a country. But it does not yet occur on an internat-
ional scale, which means patients in poor countries are denied
access to life-saving drugs because they do not have the requis-
ite cash to pay for the pills they need. Pills -- not hospitals
or expensive machines or expensive facilities for state-of-the-
art surgery. This is people dying for lack of a pill that exists
in plenty in one place but not in another place. The editors of
the New England Journal of Medicine not long ago condemned
research protocols based on such disparities, but there are
clinicians in both rich and poor countries who say a double
standard is indeed required if any progress is to be made. 
... ... E. Mbidde (Makerere Univ., UG), in an editorial in the
journal Science, calls for a double standard and states that "a
discussion of ethical principles in biomedical research that
ignores the socioeconomic heterogeneity of society is not ethical
and not worth holding", and that the International Ethical
Guidelines for Biomedical Research Involving Human Subjects, in
place since 1993, will in their present form "delay development
of badly needed vaccines and treatment regimens." QY: Edward
Mbidde, Uganda Cancer Institute, Makerere University, UG
(Science 9 Jan 98)
-------------------
Related Background:
AIDS RESEARCH IN POOR COUNTRIES: BIOETHICS REVISITED
B. Bloom (Albert Einstein College of Medicine, US), in a review
of international ethical issues in research in AIDS vaccines, the
review appearing in the same issue of Science as the editorial
mentioned in the previous report, concludes it is necessary to
clarify the existing guidelines to make clear what is attainable
for implementation in developing countries whose health care
resources are severely constrained. The author mentions only in
passing the editorial in the New England Journal of Medicine last
year that began the public discussion.
QY: Barry R. Bloom <bloom@aecom@.yu.edu> (Science 9 Jan 98)
-------------------
Related Background:
NADER GROUP CALLS AIDS TRIALS UNETHICAL
Ralph Nader's Public Citizen's Organization has charged that
international AIDS therapy trials in developing countries are
unethical. The basis of the accusation is that patients given
placebos rather than the drug AZT are compromised by not re-
ceiving the most effective treatment for the disease. Health
officials state that on the contrary the studies are ethical
and are vital for international treatment of the AIDS epidemic.
Nader held a press conference on 22 April.
(Science-Week 1 May 97)
-------------------
Related Background:
ETHICAL DILEMMAS IN THIRD WORLD CLINICAL RESEARCH
It is not often that a leading scientific journal publishes an
eight page front article and in the same issue of the journal
also publishes eight pages of editorial matter most of which
calls the front article an example of unethical research. But
that is exactly what happened last week in connection with a
study of drug therapy against tuberculosis in patients already
infected with HIV. The reported study, by Christopher C. Whalen
et al (Case Western Reserve University, US; other installations
in US and UG), took place in Uganda, and included a placebo group
of HIV infected individuals who were not given any anti-tubercul-
osis drug therapy at all (the drugs isoniazid, rifampin, pyrazin-
amide) even though these drugs have been shown in other studies
to have preventive action against tuberculosis in people who
carry tuberculosis antibodies. In the editorial matter, presented
in three separate pieces by 5 physicians, Marcia Angell, the
Executive Editor of the journal, calls into question the ethics
of the Whalen study. It appears the justification of the Whalen
study by its authors was the desire to glean definitive data con-
cerning the expected effectiveness of the known anti-tuberculosis
drugs in HIV infected patients in both the U.S. and Africa.
Angell states: "An essential 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." Everyone
apparently agrees that the study could not possibly have been
carried out in the U.S. because it would be prohibited by current
U.S. regulations. These prohibitions evidently do not exist in
Uganda. (New England J. Med. 18 Sep 97)
-------------------
Related Background:
HEAD OF NIH COMMENTS ON CLINICAL STUDIES IN THIRD WORLD
There is evidently a flap brewing concerning U.S. management of
clinical studies of diseases in developing countries in which
placebo groups are used as controls, the placebo groups receiving
no medication at all, even if such medication is available and
known to have therapeutic value. Such placebo studies in the U.S.
are not allowed, but they are allowed in many developing countr-
ies, and in the September 18th issue of the respected New England
Journal of Medicine a paper reporting such a study in Uganda by a
U.S. managed research team of the clinical effectiveness of three
anti-tuberculosis drugs in HIV infected Ugandans was published.
In the same issue of the journal, as many pages as the report
were devoted by the journal to editorial criticism of the ethics
involved. Now Harold Varmus, head of the U.S. National Institutes
of Health, which was involved in the Uganda study, and David
Satcher of the U.S. Centers for Disease Control and Prevention,
which was also involved in the Uganda study, have an article in
that journal defending such studies in developing countries. The
crux of the Varmus-Satcher position is apparently as follows:
"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." One
wishes Varmus and Satcher would have in the very next sentence
considered why, despite this "compelling" reason, such placebo
studies are not permitted in the U.S. The evident answer is that
in the U.S., the "compelling" reason has not been found compell-
ing enough. So that is the fundamental question: Why the applic-
ation of one ethical standard in the U.S. and another ethical
standard in Uganda? And this is the question addressed by the
editorial matter in the 18th September issue of the journal. The
New England Journal of Medicine has announced it will later
publish responses to the Varmus-Satcher article by Marcia Angell,
Executive Editor of the journal, who with others previously
criticized the reported Uganda study. (Our first report of the
Uganda study is in the SCIENCE-WEEK/SCIENCE-REPORT issue of 26
Sep 1997) QY: H. Varmus, National Institutes of Health, Bethesda
MD 20892-0148 US (New England J. Med. 2 Oct 97)
-------------------
Related Background:
ESTIMATED 20 MILLION INFECTED WITH AIDS IN SUB-SAHARAN AFRICA
There is perhaps too much of a tendency in many quarters to think
of a plague only as a state of affairs in which people drop dead
in expensive restaurants and get hauled away in trucks containing
piles of bodies. Our current plague, although not as dramatic as
some plagues of the past, is no less an international calamity. 
The United Nations AIDS Program recently released a report
containing the following: 
-- In 1997, 5.8 million people worldwide were newly infected with
HIV.
-- The number of new HIV infections this year rose 9% over 1996.
-- The total number of infected adults is now a little under 30
million, about 1% of the world's adult population.
-- This year, the total number of people infected with HIV
increased by 13%
-- More than 20 million people in sub-Saharan Africa are infected
with HIV, which is 7% of that adult population.
-- This year, 2.3 million people worldwide will have died of
AIDS, the consequent stage of HIV infection.
-- In South and Southeast Asia, 6 million people are infected
with HIV.
-- In Latin America, 1.3 million people are infected with HIV.
-- In North America, 860,000 people are infected with HIV.
-- In Western Europe, 150,000 people are infected with HIV.
(Nature 27 Nov 97)