THE CONDUCT OF CLINICAL TRIALS OF MATERNAL-NFANT TRANSMISSION OF HIV
SUPPORTED BY THE UNITED STATES DEPARTMENT OF
HEALTH AND HUMAN SERVICES IN DEVELOPING COUNTRIES
A SUMMARY OF THE NEEDS OF DEVELOPING COUNTRIES,
THE SCIENTIFIC APPLICATIONS,
AND THE ETHICAL CONSIDERATIONS
ASSESSED BY THE NATIONAL INSTITUTES OF HEALTH AND
THE CENTERS FOR DISEASE CONTROL AND PREVENTION
1994-1997
JULY 1997
For the past three years the United States
Department of Health and
Human Services (HHS),
through its National Institutes of Health (NIH)
and Centers for Disease Control and Prevention (CDC), has
been engaged
in the development and conduct of clinical trials
designed to identify
feasible interventions for preventing maternal-infant
transmission of
HIV in developing
countries. The Director, NIH, the Director, CDC, and
other senior scientists and administrators within the NIH and CDC, at
the request of the Secretary, HHS,
conducted a thorough assessment of
the previous reviews of the needs, resources, and health
care
capacities of these developing countries and the process of
scientific
development and ethical evaluation leading up to and guiding the
current conduct of these clinical trials. As an added
measure,
comments of a number of experts in biomedical ethics and the
biosciences outside of NIH and CDC were
also sought and considered.
Based on this assessment, NIH
and CDC have determined that, although
these are complex matters, the studies have the potential
to be of
enormous value to the developing countries and are
scientifically
well-founded and ethically acceptable.
The NIH/CDC
assessment addressed three major questions related to
these clinical trials. What is the need for these studies?
Are the
studies adequately designed to examine options for treatment
that will
meet that need? Is the involvement of human subjects in
these studies
consistent with the internationally accepted principles of
autonomy,
justice, and beneficence as implemented by the United States
Federal
Policy for the Protection of Human Subjects,
including the equitable
selection of subjects, obtaining of voluntary informed consent,
and
employing the input, review, and authorization of the
appropriate
ethical and other bodies in the
where the research is being conducted?
THE NEED
One regimen of antiretroviral therapy has
been shown to reduce
substantially the likelihood of maternal-infant transmission of
HIV.
The identification of this successful regimen
was the result of the
National Institutes of Health's AIDS Clinical
Trials Group protocol
076 (ACTG
076 or 076) in 1994. In spite of
this knowledge,
approximately 1,000 HIV-infected infants are born each day, the
vast
majority of them in developing countries. This occurs, in
part,
because the regimen proven to be effective is simply not
feasible as a
standard of prevention in much of the developing world.
There are two reasons for this lack of
feasibility. First, to follow
the regimen that has proven efficacy requires that the
women be
reached early in prenatal care; be tested for and counseled
concerning
their HIV status; comply with a lengthy oral treatment
regimen;
receive intravenous administration of the antiretroviral zidovudine
(ZDV or AZT) during
labor and delivery; and refrain from
breast-feeding. Additionally, the newborns must receive 6 weeks of
oral AZT therapy. During and after the time the mother and
infant are
treated with AZT, both must be carefully monitored for
adverse effects
of exposure to this drug. In the developing world
countries that are
the sites of these studies, these requirements could
seldom be
achieved, even under the infrequent circumstance when women
present
early enough for the screening and care requirements of the
076
therapeutic regimen to be implemented. Second, the wholesale drug
costs for the AZT in the 076 regimen are estimated to be in
excess of
$800, an amount far greater than these
developing countries could
afford as standard care. For example, in the developing
country of
pregnant woman and her child is more than 600 times the annual
health
care budget allocation for one person. Less complex and
expensive
alternatives are urgently needed to address the staggering impact
of
maternal-infant transmission of HIV in developing countries.
In June 1994, after the results of ACTG 076 were released, the World
Health Organization (WHO) convened a group of
researchers and public
health practitioners from around the world in
international panel called for the use of the 076 regimen in the
industrialized world, where it is feasible, but immediately called
for
the exploration of alternative regimens that could be
used in the
developing world, stating that logistical issues and cost would
preclude the widespread application of the 076 regimen. The
WHO panel
called for international coordination of research efforts to
develop
simpler, less costly drug regimens. This coordination
continues in the
form of meetings two to three times per year of the UNAIDS Informal
Working Group on Prevention
of Mother to Child Transmission of HIV. As
a result, there is a global research agenda addressing
the need to
devise efficacious regimens that can be safely and widely
implemented
in the developing world.
THE STUDY DESIGNS
The NIH- and
CDC-supported studies of maternal-infant transmission of
HIV in developing countries are designed to
meet the critical need
just described. The panel convened by WHO in
Recommendation 6 of its Recommendations from
the Meeting on Prevention
of Mother-to-Infant Transmission of HIV by Use of Antiretrovirals,
Since the ZDV
regimen studied in ACTG 076 is not applicable
in those parts of the world where most MTI
[mother-to-infant] transmission of HIV occurs,
placebo-controlled trials offer the best option for
obtaining rapid and scientifically valid results.
The WHO panel went on to explain in its
commentary on the
recommendation:
Most of MTI
transmission of HIV occurs in the developing
world, where the ZDV regimen used
in ACTG 076 is not
applicable because of its cost and operational requirements.
In those parts of the world, the choice of a
placebo for the
control group of a randomized trial would be appropriate as
there is currently no effective alternative for
HIV-infected
pregnant women.
For each individual study there has been
careful consideration of the
specific needs of and treatment feasibility within the country
in
which it would be implemented. NIH,
CDC, collaborating
institutions, and the host countries will continue to monitor each
study and any changes in the countries that may have an
impact on
study design. 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. Nor
does the standard of care for these HIV-infected women
include the
combination therapies recommended and used for some HIV-infected
women
in the
performance-site standard in the form of placebo controls provides the
direct comparison of standard and new intervention that is
needed to
form the basis for rational policy decisions and 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.
The NIH- and
CDC-supported studies are designed in a manner consistent
with the still-pertinent recommendations of the WHO panel
and have
been developed in on-site collaboration with the health
ministries,
physicians, and researchers of the host countries. There is
strong
support for the design of the NIH-
and CDC-supported studies,
including the placebo arms, within the countries where the
clinical
trials are being carried out, in part because the studies
are
assessing regimens that might realistically be employed to
decrease
mother-to-infant transmission, taking into account the health care
resources and operational capabilities of these countries.
HUMAN RESEARCH SUBJECT PROTECTIONS
The acceptability of the involvement of human
subjects in the studies
under discussion has been scrupulously reviewed beginning
with the
first proposal for ACTG 076 which
was a placebo-controlled study
conducted in the
regimen was proven successful, the WHO conference in
issued clear guidelines for research taking into account the
extremely
wide range of health care capabilities that characterize
the broad
spectrum of countries described by the term developing
countries. As
mentioned earlier, these matters have been debated in formal
discussions, forums, and required reviews in the
international settings, and in the countries where the clinical
trials
are or will be carried out.(1) Even so, CDC determined
that Assurances
for performance site countries required by HHS regulations at Title
45, Part 46, Section 103 had not been
obtained prior to enrolling
subjects. CDC acted immediately to notify OPRR
and to address these
administrative procedures. The Assurances for the CDC-Thailand and
CDC-Cote
7, 1997 and
protection administrative procedures to be in full compliance
with 45
CFR 46.103.
Arguments against the NIH-
and CDC-supported studies appear to rest on
the proposition that it is unethical to conduct a
clinical trial
unless it offers all participants a chance to receive an
effective
intervention if such is available anywhere in the world, even if
it is
not available at the site of the clinical trial. Ideally,
this would
be so for all clinical trials for all therapies. But the
reality is
that often it is not possible. The very purpose of the NIH- and
CDC-supported studies of maternal-infant
transmission of HIV in
developing countries is to identify interventions other than
those of
076 and we agree with the WHO Geneva panel's Recommendation
2 that:
It should be emphasized that the results of ACTG 076 are
only directly applicable to a specific population.
Moreover,
the ZDV regimen employed in the
ACTG 076 study has a number
of features (cost, logistical issues, among others) which
limit its general applicability. Therefore, no global
recommendations regarding use of ZDV to
prevent MTI
transmission of HIV can be made.
The use of historical controls was considered
and found to be
unacceptable because existing epidemiological data for the host
countries are inadequate for this purpose. We agree with the
commentary on Recommendation 5 of the WHO Geneva panel that:
Randomized controlled trials offer the best
evaluation of
new treatment regimens. The use of historical controls is
strongly discouraged, due to the wide changes with time in
the study population (differences in the distribution of
disease stages), the circulating viral strains, the
diagnostic tools used for the ascertainment of the HIV
infection status of infants (antibodies in earlier cohorts
compared to direct viral markers in more recent cohorts),
and the treatment practices (increased use of zidovudine in
HIV-infected pregnant women with AIDS-related
symptoms
and/or CD4+ lymphocyte
counts).
The WHO guidelines clearly indicate that the
in-country health care
capabilities of each country in which maternal-infant HIV
transmission
research is to be conducted must be used to define the type of
research which is ethical and therefore permissible in that
country.
If a country will be able to afford only very
minimal increments in
the resources directed toward improved perinatal care for HIV-infected
pregnant women and their children, then trials like those
focused on
vitamin A and other micronutrients are ethical, permissible,
and
desirable.
In other countries, such as
complex.
AZT/076-like regimen. However, Thai researchers, physicians, and
public health officials are understandably interested in
seeing a
number of issues addressed before any AZT is placed in
general use in
HIV-infected pregnant women in their country:
(1) Is a much simplified
076-like regimen (e.g., initiation of
prenatal treatment at 36 weeks
of pregnancy, oral instead of intravenous AZT during
labor and
delivery, elimination of AZT given to the infant) effective in
reducing transmission? (2) What adverse outcomes related to
AZT use
will be seen in Thai populations? Will adverse effects not
seen in the
Thai women safe and
well-tolerated? Do Thai women
metabolize AZT such
that the dose used is the right one to use in all Thai
HIV-infected
pregnant women? and, (4) How does the
type of HIV seen in
(which has
demonstrable differences from the type seen in the
respond to AZT?
Seeking answers to these questions are two
studies, one supported by
CDC and one supported by NIH.
The CDC-Thai study will determine how
well tolerated and how effective a very simple AZT regimen
is in a
population of women who are infected with a subtype of HIV
predominantly different from that observed in the
have co-factors for transmission that may differ from
those seen in
American populations. Because it is a two-arm, placebo-controlled
clinical trial, the CDC-Thai study will provide rapid answers
to many
of the important questions noted above. It also will
enable the
Ministry of Health and physicians in
decisions about the use of a much-simplified AZT regimen for
general
use in HIV-infected pregnant women.
Complementing the CDC-Thai study is an NIH-Thai study to determine how
much additional benefit, as compared to how much additional
cost and
adverse effect, is occasioned by small increments in
treatment
complexity. The NIH-Thai study has
four arms, each a modest increment
over the treatment arm in the CDC-Thai study. However,
even the most
complex arm of the NIH-Thai study
is not identical to the treatment
arm of 076. The NIH-Thai study
will benefit from the baseline that is
established by the CDC-Thai study.
Since the NIH-Thai
study provides some level of AZT to all
participants, the data from the CDC-Thai study would be particularly
important for interpretation of results if the outcomes were
the same
for each of the four arms. Taken together, these two
studies will
provide a broad range of information about the likely value
of AZT as
a strategy to interrupt maternal-infant transmission of
HIV.
In an analysis of the spectrum of studies
supported by the NIH and CDC
in
guidelines, including the recent WHO guidelines which address
specifically the ethical conduct of research in the post-076 era.
The
primary consideration in decisions about the appropriate
conduct of
research has been this: Once the research is completed at a
given
site, will the population which the study participants
represent be
able to profit from what is learned from that research?
The International Ethical Guidelines for
Biomedical Research Involving
Human Subjects that were prepared by the
Council for International
Organizations of Medical Sciences (CIOMS) in collaboration with WHO
are:
...intended to indicate how the ethical
principles embodied
in the Declaration [of
applied in developing countries.
To evaluate interventions that they could not
implement realistically
would be exploitive of those in the participant country
since there
would be no likelihood of meeting requirement 15 of the
Guidelines
that obliges:
...any product developed [through] such
research will be
made reasonably available to the inhabitants of the host
community or country at the completion of successful
testing...
Therefore, we have determined that the more
compelling ethical
argument is against using a regimen that if found to be
superior in
the study could not possibly be used in the prevention of
maternal-infant transmission of HIV in the host country. Turning once
again to
the conduct of a study involving a full course regimen of
AZT (such as
that used in ACTG 076) because
they believed it would be unethical to
undertake such a study in
and poor health infrastructure make the introduction of
AZT as
standard treatment for HIV-infected pregnant women unfeasible.
Instead, the health officials wanted research
on alternative treatment
approaches that might reduce maternal-infant transmission of
HIV. The
justification and ethical foundation for the NIH-
and CDC-supported
studies incorporate the reality that the clinical trials are
examining
other alternatives that could actually be used for the
majority of
HIV-infected pregnant women and mothers in
the countries in which the
clinical trials are being carried out. The process of ethical
review
of these trials has been rigorous. It has included
community and
scientific participation and the application of the
protection of human research subjects in reviews by the relevant
institutional review boards (IRBs) in the
U.S. and in the countries
where the clinical trials are carried out.
governments has been obtained and each active study has been and
will
continue to be reviewed by an independent Data and Safety
Monitoring
Board. These studies are in compliance with broadly accepted
principles of ethics of international research, in which the
need to
take into account the reality of available and feasible
health care is
a consideration of substantial importance.
In summary, these studies all address an
urgent need in the countries
in which they are being conducted. They have been
developed with
extensive in-country input and participation, and they are
consistent
with widely accepted principles and guidelines of
bioethics. Our
perspective and our decision to support these trials rest heavily
on
local support and approval. In this regard, we point to the
words of
Edward K. Mbidde,
Chair, AIDS Research
Institute, in a letter, dated
These are Ugandan studies conducted by
Ugandan investigators
on Ugandans. [Elsewhere in the letter he discusses
Ugandan
ethical review.] Due to lack of resources we have been
sponsored by organizations like yours [NIH].
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
but Ugandans conducting their study on their people for
the
good of their people.
The issues surrounding these studies are,
indeed, complex and subject
to some disagreement. However, final judgments about
their
appropriateness must be heavily weighted in favor of decisions made
at
the local level, as long as those decisions are
consistent with
international standards and those of the
to realistically and rapidly address the gravity of
mother-to-infant
transmission of HIV in the developing world and the current lack
of a
proven, feasible intervention against it, than to continue
the studies
on which our two agencies have embarked.
DATED:
[Image] [Image]
Harold Varmus David
Satcher
Director, National Institutes of Director,
Centers for Disease Control
Health and Prevention
Appendix:
Recommendations From
The Meeting On Mother-To-Infant
Transmission Of HIV
By Use Of Antiretrovirals,
----------------------------------------------------------------------
1A useful exploration of these events is
contained in an article
written by Jon Cohen and published in Science, Vol. 269, pp.
624-626,